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- Obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or
- Obtains, uses, studies, analyzes, or generates identifiable private information or identifiable biospecimens.
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- Meets the US Department of Health and Human Services (HHS) definition of research and involves human subjects as defined in the HHS regulations; and/or
- Meets the Food and Drug Administration (FDA) definition of research and involves human subjects as defined in FDA regulations.
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- Determine if the activity meets the definition of research. Some activities such as QA/QI projects or types of scholarly and journalistic activities may not be research under the 2018 Common Rule. Please see the definition of research in the regulations (2018 requirements) for an expanded list of activities that are deemed not to be research under these regulations.
Next, determine if the research is being conducted with living human subjects. If not, no IRB review is required because research with identifiable specimens and/or data from deceased individuals falls under the category of not human subjects research.
Footnote There is an exception to this statement when the safety and/or efficacy of Invitro Diagnostic Devices are being studied. In such cases, the FDA does not differentiate whether the specimens are from living or deceased individuals.
There is an exception to this statement when the safety and/or efficacy of Invitro Diagnostic Devices are being studied. In such cases, the FDA does not differentiate whether the specimens are from living or deceased individuals.
- Research that includes living human subjects as described above, or that meets the definition of clinical trial or clinical investigation above, is considered human subjects research that requires that a protocol be submitted in the electronic IRB management system for IRB review or consideration of an exemption from IRB review.
- See the following flow diagram:
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- If the research is "not human subjects research," a formal determination by OHSRP is not mandatory for research activities involving only use (including secondary use study or analysis) of coded or de-identified (not individually identifiable) human specimens and/or data.
- Investigators should assess whether their research meets the regulatory definition of human subjects research. If an investigator is not certain, a request for a formal determination may be made through the NIH electronic IRB system.
- If a formal determination that an activity is not human subjects research is needed or desired, only OHSRP or the Office of IRB Operations (IRBO) can make a formal determination that an NIH IRP activity is not human subjects research.
- There may be other special research considerations per NIH policies or additional requirements for the review of research that apply, e.g., those involving human fetal tissue or human stem cells.
- If the protocol involves conducting research with data or biospecimens, consider whether these are individually identifiable under federal regulations for the protection of human subjects.
- As a general rule, if gaining access to identifiable information is more involved than either using a key that links coded information to identifiers or combining information that is either already in the possession of the investigator or easily accessible to the investigator, the investigator may not be considered to be in possession of individually identifiable information. Certain demographic or clinical characteristics of the subjects may impact whether their data or biospecimens are individually identifiable to an investigator, e.g., the sample size; the location of the original collection (i.e., small town or the zip code); the disease or condition being studied, particularly if a rare disease; and membership in a unique cultural group. If an investigator has a prior relationship with the subjects and is able to re-identify the data based on past experience with the subjects or the data set, NIH considers the data to be identifiable to them. Investigators should consult with OHSRP if they are unsure whether data or biospecimens being used in a specific research project would be considered individually identifiable. The following elements (either individually or in combination) may constitute an identifier (i.e., the identity of the subject is or may readily be ascertained by the investigator or associated with the information). The list below is not intended to be exhaustive:
- Names (or initials)
- Street address or geocode data
- Date of birth
- Telephone numbers
- Fax numbers
- Electronic mail addresses
- Social security numbers
- Medical record numbers
- Health plan beneficiary numbers
- Account numbers
- Certificate/license numbers
- Vehicle identifiers and serial numbers, including license plate numbers
- Device identifiers and serial numbers
- Internet protocol (IP) address numbers
- Biometric identifiers, including finger and voice prints
- Full face photographic images and any comparable images
- Any other unique identifying number, characteristic, or code (when a key to the identifier/characteristic/code is readily accessible to the investigator or given the context or circumstance could make a participant identifiable to the researcher)
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- Includes research with identifiable specimens and/or data or with coded specimens and/or data for which the investigator has the code key. When identifiable biospecimens or data are used to address new aims or to conduct new research analyses (not explicitly described in the current IRB approved protocol), the PI should write and submit a new protocol to the IRB.
- When an investigator conducts secondary research with coded and linked biospecimens or data and will generate individual subject level results that he or she can link back to the research subjects, this is considered human subjects research requiring prospective IRB review and approval.
- When there are collaborations with external researchers in which the NIH investigator shares coded and linked biospecimens or data for secondary research and receives coded and linked results that link back to individual subjects, IRB review and approval is needed.
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- All non-exempt secondary research requires either that consent be obtained from the prospective participants or that the IRB grant a waiver of informed consent.
- Note: If the proposed research is within the scope of the aims and objectives described in the open and IRB approved research protocol, it is not considered secondary research and new consent or a waiver of consent is not necessary.
- Note: If the proposed research is within the scope of the aims and objectives described in the open and IRB approved research protocol, it is not considered secondary research and new consent or a waiver of consent is not necessary.
- For the IRB to grant a waiver of consent; the following considerations apply:
- The research must meet the regulatory requirements for a waiver at 45 CFR 46.116(f)(3).
- The proposed research must be consistent with the terms of the initial consent (if any) under which the specimens and/or data were collected.
- For example, the initial consent states that the samples/data may be used in the future for any biomedical or health related research.
- For example, the initial consent states that the samples/data may be used in the future for any biomedical or health related research.
- If the proposed research is not consistent with the terms of the initial consent, the IRB may require reconsent of participants in order for their specimens and/or data to be used.
- Examples of terms that would not be consistent include:
- If the initial consent said the samples would not be used for any future research;
- If the consent stated that the samples would only be used for specific types of research and those differ from the proposed research; or
- If it stated the samples would be destroyed after the initial research was completed.
- Examples of terms that would not be consistent include:
- If the original consent form was silent with regard to future research, or informed consent was not obtained at the time of the original collection (e.g., biospecimens were collected for clinical diagnostic purposes/pathological waste from surgery), the PI can either obtain new consent from the participants or describe to the IRB why the conditions for a waiver of consent are met and why it is needed to conduct the research (See the section of this manual that describes criteria that need to be met for the IRB to approve waiver of consent.)
- If the secondary research will involve genetic testing or sequencing or other types of genetic research, or use for drug development, subjects must have explicitly consented to this.
- If the biospecimens and/or data may be used for commercial profit, the consent must address this as well as whether the subject will or will not share in the profit.
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* Secondary research: research use of biospecimens or data for other than the original purpose(s) for which the biospecimens or data were initially collected through interaction or intervention with living individuals
1 If you will receive research results that you can link back to identifiers after sharing specimens or data, the project is considered to be human subjects research. You must submit a secondary research protocol to address the planned research and seek IRB approval prior to initiation of the activities. The protocol must include new consent or a justification of a waiver of consent for the planned research.
2 In some circumstances, it may be appropriate to re-consent the subject to allow their specimens and data to be shared. Consult the IRB if you wish to proceed with sharing.
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- Ensure that the original consent form addresses sharing for future research; and
- Ensure that the consent language is consistent with the planned research or allows for broad future research.
- If the original consent form does not contain language about sharing for future research ("is silent"), the investigator should reach out to the IRB Chair who will determine whether sharing is permissible or not.
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- Best Practices for the Approval and Conduct of Secondary Research, including Repositories (7/9/19) Slides and Videocast;
- When IRB Approval is Necessary and How to Complete the New Investigator Attestation for Tech Transfer Agreements (3/18/20) Slides and Videocast
- Secondary Research: Fact, Fiction, Fears and Fantasies (January 19, 2021) Slides and Videocast: What Constitutes Secondary Research and When is IRB Review Required for This Research?
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- Some research which involves human subjects may be exempt from IRB review if it falls into one of the specific categories of exempt research.
- Investigators who wish to conduct exempt human subjects research must submit the project in the NIH IRB electronic IRB system and receive a formal determination of an exemption before commencing any research activities. At NIH, only designated staff in IRBO can make a determination that research is exempt.
- In order to be exempt, certain human subjects research subject to the 2018 Common Rule may require limited IRB review.
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- Specific types of research conducted in educational settings that involves certain normal educational practices, such as research on instructional techniques already in use or classroom management. (This type of research is not regularly conducted at NIH.)
- Interactions involving educational tests, surveys, interviews, or observation of public behavior if specific criteria are met. This exemption does not apply to survey or interview research with children or research involving public observation of children, when the researcher participates in the activities being observed.
- Benign behavioral interventions that meet specific criteria and that are brief in duration, harmless, painless, and not physically invasive, and not likely to have a significant adverse lasting impact on subjects or be offensive or embarrassing to subjects. This exemption is not applicable to research involving children.
- Secondary research of identifiable private information or identifiable biospecimens, if at least one of the following criteria is met: when the identifiable materials are publicly available, or when the data is recorded by the investigator in a de-identified manner, i.e., no identifiers are accessible to the researcher once the analysis begins. Additional provisions apply.
Public benefit or service programs.
Footnote This type of research is not commonly conducted by NIH investigators and includes the following: Research and demonstration projects that are conducted or supported by a Federal department or agency, or approved by the relevant department/agency head and that are designed to study, evaluate, improve, or otherwise examine public benefit or service programs, including procedures for obtaining benefits or services under those programs, possible changes in or alternatives to those programs or procedure OR possible changes in methods or levels of payment for benefits or services under those programs.
- Taste and food quality evaluation and consumer acceptance.
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- The answer is "it depends."
- Many quality improvement efforts are not research subject to the HHS protection of human subjects regulations and would not require IRB review. However, in some cases quality improvement activities are designed to accomplish a research purpose as well as the purpose of improving the quality of care, and in these cases, the regulations for the protection of subjects in research (45 CFR part 46) may apply.
- QA/QI activities such as implementing a practice to improve patient care or collecting patient or provider data for non-research clinical or administrative purposes, do not meet the definition of research under the Common Rule. Nor would QI activities that are limited to delivering health care, or measuring and reporting provider performance data for clinical, practical, or administrative purposes.
- In other cases, QI projects may constitute nonexempt human subject research such as when a project involves using an untested intervention which includes collection of information about patient outcomes to establish scientific evidence to determine how well the intervention achieved its intended results.
- Planning to publish an account of a quality improvement project does not necessarily mean that the project fits the definition of research. Conversely, a quality improvement project may involve research even if there is no intent to publish the results.
- See OHRP Quality Improvement Activities FAQs for more information.
- Also see OHSRP guidance document, QA/QI vs. Research: Do I Need to Submit for an Exemption or IRB Approval? on the OHSRP webpage Step 1: Do you need to submit to the IRB?
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- The answer is (again) "it depends."
- The Centers for Disease Control and Prevention define program evaluation as the systematic collection of information about the activities, characteristics, and outcomes of programs to make judgments about the program (or processes, products, systems, organizations, personnel, or policies), improve program effectiveness, and/or inform decisions about future program development.
- Key concepts in considering program evaluations as they relate to IRB review:
- Program evaluations may be considered research when there is a hypothesis or question being answered, and the information being collected is designed to contribute to generalizable knowledge (i.e., beyond the context of the specific institution(s) conducting the evaluation).
- Whether these projects are research is determined by the IRBO on a case-by case-basis.
- The IRBO makes this determination by evaluating a group of factors including the purpose and intention of the project, level of risk, and methodology.
- Publishing or presenting program evaluation findings does not automatically mean the project is research.
- For additional information and a helpful table that differentiates characteristics that may make such projects research activities requiring submission for an exemption or IRB approval see the document labeled Program Evaluation vs. Research found on the OHSRP webpage Step 1: Do you need to submit to the IRB?.
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- All requests for exemptions must submitted via the electronic IRB system.
- Requests for exemption are broken into two different categories based on the type of research being performed. Each category has its own template and set of instruction on the IRBO Protocol Templates and Forms webpage. The two categories are:
- Retrospective Data or Biospecimen Review
- Collecting Prospective Data from Humans
- After determining which type of exempt research applies, download both the applicable instructions and protocol template here. Please review the instructions and the template carefully. Use the provided template to create a complete protocol to ensure that you have included all the required elements.
- Requests for exemptions are submitted in the electronic IRB system. The instructions from the IRBO website walk you through the process.
- If your project is Determined to be Exempt from IRB Review, you will receive an outcome letter informing you that your research has been confirmed as Exempt Human Subjects Research. The letter will provide you the applicable exemption category and further instructions on possible future responsibilities.
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- Instructions and Protocol Template for Retrospective Data or Biospecimen Review
- Instructions and Protocol Template for Prospective Data Collection from Humans
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- Non-exempt human subjects research may be approved by the NIH IRB only when all required regulatory and policy criteria are met.
- NIH investigators may not begin research activities until all required approvals have been obtained (e.g., institutional approvals, as applicable, and approvals from IRB, and ancillary committees).
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- Some human subjects research may possibly be eligible for expedited review if it does not involve research with prisoners.
- Most minimal risk studies are reviewed by an expedited reviewer. The categories that allow for Expedited Review of Research are further described in this complete list from OHRP. The following is a summary of the categories:
- Category 1: Clinical studies of drugs and medical devices only when either of the two conditions below is met.
- Research on drugs for which an investigational new drug (IND) application (21 CFR Part 312) is not required.
- Clinical studies of medical devices for which an investigational device exemption application (21 CFR Part 812) is not required, or the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.
- Category 2: Collection of blood specimens by finger stick, heel stick, ear stick, or venipuncture as follows:
- From healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 mL in an 8-week period and collection may not occur more frequently than 2 times per week.
or - From other adults and children, considering the age, weight and health of the subjects, 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 per kg in an 8-week period and collection may not occur more frequently than 2 times per week.
- From healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550 mL in an 8-week period and collection may not occur more frequently than 2 times per week.
- Category 3: Prospective collection of biological specimens for research purposes by noninvasive means. See this category in OHRP document for more details: Expedited Review: Categories of Research that may be Reviewed Through an Expedited Review Procedure
- Category 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.
- Category 5: Research involving materials (data, documents, records, or specimens) that have been collected, or will be collected solely for non-research purposes (such as medical treatment or diagnosis)
- Category 6: Collection of data from voice, video, digital, or image recordings made for research purposes
Category 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.
Footnote NOTE: Some research in this category may be exempt from the HHS regulations for the protection of human subjects. See 45 CFR 46.101(b)(2) and (b)(3). This listing refers only to research that is not exempt.
- Category 8: All greater than minimal risk studies will be reviewed by a fully convened IRB unless it falls under one of these Expedited Continuing Review Categories:
- Continuing review of research previously approved by the convened IRB where the research is permanently closed to the enrollment of new subjects; (ii) all subjects have completed all research-related interventions; and (iii) the research remains active only for long-term follow-up of subjects.
- Continuing review of research previously approved by the convened IRB where no subjects have been enrolled and no additional risks have been identified. (An example would be if there was a new risk added to the Investigational Brochure.)
- Continuing review of research previously approved by the convened IRB where the remaining research activities are limited to data analysis.
- Category 9: Continuing review of research, not conducted under an IND or IDE where categories 2-8 above 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. (This means that this category applies if the protocol does not fit in one of the above categories and is minimal risk but was initially be reviewed by the Full Board to allow Category 9 to be used.)
- Category 1: Clinical studies of drugs and medical devices only when either of the two conditions below is met.
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- Approve as submitted: The convened IRB, the expedited reviewer, or the limited IRB reviewer approves the research study.
- Modifications Required to Secure Approval: The convened IRB, or the expedited reviewer, or the limited IRB reviewer approves the research study contingent on stipulated changes to the research.
- Defer: The convened IRB determines that a research study requires resolution of one or more criteria for IRB approval of research at § 46.111, or other substantive issues have been identified (e.g., risks have not been identified, risks are significant and have not been adequately minimized, or the safety monitoring plan is not adequate). When such an action is taken, the IRB may stipulate substantive changes to the research study. Deferred actions must be reviewed by the convened IRB in order to be approved.
- Disapprove: The convened IRB determines that a research study cannot be approved in its present form or is inappropriate based on its present design (e.g., for reasons such as subject safety or scientific validity).
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