HRPP Policy - IRB review process

The IU IRBs are charged with protecting the rights and welfare of human research subjects, specifically ensuring that those individuals participating in research are not subject to undue or inappropriate risks, that participation remains a voluntary right, and that the conduct of research is upheld as a privilege.

The Belmont Report identifies basic principles and guidelines that address ethical issues arising from the conduct of human subjects research.  These principles - autonomy/respect for persons, beneficence, and justice – form the cornerstone of federal regulations involving human subjects. These principles are to be upheld by all individuals involved in human subjects research: researchers and research staff, the Institutional Official (IO) for research, and the IRB and IRB support staff.

IU applies the federal regulations for protection of human subjects (45 CFR 46, Subpart A, Protection of Human Subjects, also known as “the Common Rule”) when research is sponsored or overseen by a federal agency.

When studies do not receive funding from, or are not otherwise regulated by, a federal agency, IU has adopted policies and procedures to accommodate differences in types of research and to reduce unnecessary administrative burdens.  In these instances, IU has adopted equivalent protections for subjects.

Additional federal, state, and local laws, regulations, and requirements may apply.  When laws or regulations differ or conflict, the stricter requirements are followed.

Pursuant to 45 CFR 46.103(a), each institution engaged in research that is governed by the Common Rule (45 CFR 46) and conducted or supported by a federal department or agency shall provide written assurance satisfactory to the department or agency head that it will comply with the requirements set forth in the regulations.  IU and their affiliates provide this assurance in the form of a Federalwide Assurance approved by the Office for Human Research Protections (OHRP).

The authority to develop, implement, and monitor all human subjects protection programs has been designated by the President of Indiana University to the Vice President for Research, who serves as the IO for research.  The IU IRBs are authorized by the IO to review human subjects research in accordance with the IU Policy on Research with Human Subjects.  The IRB functions independently of other organizational entities in protecting research subjects.

The Vice President for Research is also the leader of the Human Research Protection Program (HRPP) and has responsibility and authority for implementation of this program. The Vice President for Research relies on HRPP staff for knowledge of the regulations and day-to-day operations and is directly involved in allocation of resources to the HRPP. The Vice President for Research employs mechanisms to ensure that:

• Human participants are provided protections,
• The HRPP is provided support,
• The HRPP functions independently and free from coercion and undue influence,
• Legal counsel not conflicted by other organizational responsibilities is made available to the HRPP,
• Access to senior officials of the organization, when the IRB deems it to be warranted, is made available to the HRPP,
• The IRBs’ work and meeting spaces are evaluated and resources adjusted when necessary,
• Educational programs for HRPP staff and IRB members are provided and the development of HRPP Policies are supported, and
• The IRBs function independently of other organizational entities.

As appropriate, the Vice President for Research delegates responsibility for carrying out the day-to-day operational duties of the HRPP to the Associate Vice President for Research Compliance and/or the University Director, HRPP.

Prior to research initiation, the IRB review must find that all criteria for IRB approval outlined below are met, or grant exemption, as applicable.  The IRB evaluates whether resources are adequate to protect subjects’ rights and welfare, including but not limited to, PI qualifications and adequate research facilities.

The IRB may approve, require modification to secure approval (“provisionally approve” or “table”), or disapprove research proposals covered by this policy, including exemptions requiring the IRB conduct a limited IRB review to make the determination required by the IU HRPP Policy on Exempt Research.

No official or office of the institution may approve a research activity that has been disapproved by the IRB, and no external body or official may override IRB disapprovals, nor apply undue pressure on the IRB to approve a research study or reverse a decision. IRB members or HRPP staff who feel they are being unduly influenced should report this to the University Director, HRPP or to the Research Integrity Officer. Either of these officials may investigate and take corrective action, as necessary.

Research which is approved by the IRB may be disallowed by the institution. If research is approved by the IRB but not permitted by the institution, the appropriate institutional authority will promptly notify research personnel and the IRB that the research cannot be conducted, including the reasons for that determination.

The IRB may suspend, place restrictions upon, or terminate approval of research activities falling within its jurisdiction that are not being conducted in accordance with IRB requirements or that have been associated with unexpected serious harm to subjects.

The IRB may have the consent process or the research procedures of any research study under its jurisdiction observed by a third party if the IRB determines that such observation is indicated. This is typically done by the IU Quality Improvement Office.

Deliberations, decisions, findings, and actions of the IRB associated with research activities are considered confidential, except as appropriate. This information is reported to appropriate institutional officials as required by law and/or policies of the IRB. Failure to adhere to this provision may be cause for removal of a member from the IRB. See the Indiana Public Access Counselor (http://in.gov/pac/) for additional information regarding the Open Door Law and Public Records Act.

Based on the IRB's review of information provided by the study team, and in accordance with appropriate regulations and IU and IU HRPP Policies and procedures, the IRB may grant approval of research, including initial review, continuing review, and modifications to previously approved research, if it determines that all of the following requirements are satisfied:

• Risks to subjects are minimized by using procedures that (1) are consistent with sound research design and that do not unnecessarily expose subjects to risk, and (2) whenever appropriate, by using procedures already being performed on the subjects for diagnostic or treatment purposes.
  • This includes assessing the adequacy of the setting or facilities where the research will take place.
• Risks to subjects are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result. In evaluating risks and benefits, the IRB should consider only those risks and benefits that may result from the research (as distinguished from risks and benefits of therapies/procedures/activities subjects would receive even if not participating in the research). The IRB should not consider possible long-range effects of applying knowledge gained in the research (e.g. the possible effects of the research on public policy) as among those research risks that fall within the purview of its responsibility.
• Selection of subjects is equitable. In making this assessment, the IRB should take into account the purposes of the research and the setting in which the research will be conducted. The IRB should be particularly cognizant of the special problems that involves a category of subjects who are vulnerable to coercion or undue influence, such as children, prisoners, adult individuals lacking consent capacity, or economically or educationally disadvantaged persons.
• Informed consent will be sought from each prospective subject or the subject's legally authorized representative in accordance with and to the extent required by relevant regulations and IU HRPP Policies and procedures.
• Informed consent will be appropriately documented, or appropriately waived, in accordance with relevant regulations and IU HRPP Policies and procedures.
• When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.
• When appropriate, there are adequate provisions to protect the privacy of participants and to maintain the confidentiality of data.
• When some or all the subjects are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, adult individuals lacking consent capacity, or economically or educationally disadvantaged persons, additional safeguards have been included in the research proposal to protect the rights and welfare of these subjects.

The IRB may use an expedited review procedure to review any of the following:

• Research which involves only procedures listed in one or more of the Expedited Research Categories below, and which the reviewer determines involves no greater than minimal risk
• Renewals or modifications to research previously approved under expedited procedures provided the research continues to meet the Expedited Research Categories below and any modifications do not substantially increase risk to subjects
• Minor changes in research previously approved by the convened IRB

The IRB may not use an expedited review procedure to review any of the following:

• Research in which identification of the subjects and/or their responses would reasonably place them at risk of criminal or civil liability or be damaging to their financial standing, employability, insurability, reputation, or be stigmatizing, unless reasonable and appropriate protections will be implemented so that risks related to invasion of privacy and breach of confidentiality are no greater than minimal
• Classified research involving human subjects
• Studies involving randomized use of drugs, devices, or biologics. All such studies are reviewed by the convened IRB.

Research involving prisoners may be reviewed via expedited procedures, unless subject to Department of Defense requirements, if:

• For research involving interaction with prisoners, the primary IRB reviewer and the prisoner representative determine the research is minimal risk for the prison population being studied or included.
• For research that does not involve interaction with prisoners, the primary IRB reviewer determines the research poses minimal risk for the prison population being studied or included.

The following expedited categories may be applied to all human subjects research, as applicable.

Category 1

Clinical studies of drugs and medical devices only when either condition below is met:

1. Research on drugs for which an investigational new drug application (21 CFR 312) is not required. Note: Research on marketed drugs that significantly increases the risks or decreases the acceptability of the risks associated with the use of the product is not eligible for expedited review; or
2. Research on medical devices for which (1) an investigational device exemption application (21 CFR 812) is not required; or (2) 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 samples by finger stick, heel stick, ear stick, or venipuncture as follows:

1. From healthy, nonpregnant adults who weigh at least 110 pounds. For these subjects, the amounts drawn may not exceed 550ml in an 8 week period and collection may not occur more frequently than 2 times per week; or
2. 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 50ml or 3ml per kg in an 8 week period and collection may not occur more frequently than 2 times per week.

Category 3

Prospective collection of biospecimens for research purposes by noninvasive means. Examples include:

• Hair and nail clippings in a nondisfiguring manner;
• Deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction;
• Permanent teeth if routine patient care indicates a need for extraction;
• Excreta and external secretions (including sweat);
• Uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gumbase or wax or by applying a dilute citric solution to the tongue;
• Placenta removed at delivery;
• Amniotic fluid obtained at the time of rupture of the membrane prior to or during labor;
• Supra- and subgingival dental plaque and calculus, provided the collection procedure is not more invasive than routine prophylactic scaling of the teeth and the process is accomplished in accordance with accepted prophylactic techniques;
• Mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; or
• Sputum collected after saline mist nebulization.

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. (Studies intended to evaluate the safety and effectiveness of the medical device are not generally eligible for expedited review, including studies of cleared medical devices for new indications). Examples include:

• 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;
• Weighing or testing sensory acuity;
• Magnetic resonance imaging;
• Electrocardiography; electroencephalography, thermography detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and echocardiography;
• Moderate exercise, muscular strength testing, body composition assessment and flexibility testing where appropriate given the age, weight, and health of the individual.

Category 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). Note that some research in this category may be exempt from the federal regulations or IU HRPP Policy and procedure. This listing refers only to research that is not exempt.

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. ; Note that some research in this category may be exempt from federal regulations or IU HRPP Policy and procedure. This listing refers only to research that is not exempt.

Category 8

Continuing review (i.e., renewal) of research previously approved by the convened IRB as follows:

1. where (i) 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; or
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.

Category 9

Continuing review (i.e., renewal) of research, not conducted under an investigational new drug application or investigational device exemption, where categories two (2) through eight (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.

In addition, the following flexible expedited categories may be applied to research that the reviewer determines involves no greater than minimal risk and are not federally-funded, FDA-regulated, and/or subject to VA regulations, as applicable. 

Category 200

1. Collection of blood samples by IV, port, or central line that is already placed as part of regular clinical care that otherwise meets the frequency and total amount under Category 2; or
2. Collection of blood samples more frequently than permitted under Category 2, provided the total amount does not exceed what is allowed under Category 2.

Category 300

Prospective collection of biospecimens from non-facial, non-genital skin punch biopsy with allowable local anesthesia and limited to 2mm in diameter and not requiring sutures.

Category 400

1. Research involving ionizing radiation to not exceed radiation dose level 1 annually (i.e., annual effective dose (E) < 5 mSv or E < 500 mrem); or
2. Exercise interventions involving healthy individuals not involving invasive procedures, except collection of blood as described in Categories 2 and 200.

Category 500

Research involving secondary use of materials (data, documents, records, or specimens) collected for purposes of another research study. Note that some research in this category may be eligible for review under Category 5. This listing refers only to research that is not eligible for review under Category 5.

Category 700

1. Research interventions that are intended as treatment of mental health illnesses, disorders, and/or conditions and do not involve invasive procedures or input of significant amounts of energy into the subject; or
2. Food and diet interventions, excluding research involving medical foods as such term is defined by the FDA.

The IRB conducts continuing review of research at intervals appropriate to the degree of risk, but not less than once per year for:

• Non-exempt studies subject to FDA or DOJ regulations
• Research requiring review by the convened IRB, except as described below

The IRB is not required to conduct renewal for the following:

• Research granted exemption, including exempt research requiring a limited IRB review per the IU HRPP Policy on Exempt Research
• Research that is not subject to FDA or DOJ regulations and is eligible for expedited review under Categories 2-7 above
• Research that is not subject to FDA or DOJ regulations and requires review by the convened IRB, but has progressed to the point that it involves only one or both of the following:
  • Data analysis, including analysis of identifiable private information or identifiable biospecimens (i.e., data analysis only)
  • Accessing follow-up clinical data from procedures that subjects would undergo as part of clinical care (i.e., clinical follow-up)

Any proposed changes in approved research must be reviewed and approved by the IRB prior to implementation to ensure that the modified research continues to meet the criteria for approval, except when it is necessary to implement changes to eliminate apparent immediate hazards to the subjects. In this situation, the changes must be promptly reported in accordance with the IU HRPP Policy on Reportable Events.

Closure of human subjects research must be reported to the IRB within a reasonable timeframe after completion of the research (or a decision that IRB-approved research will not be initiated). 

Completion of the research occurs when:

• All research interventions and interactions with subjects have concluded, and
• All data collection and analysis of identifiable data is complete.

Multi-center research studies may be closed when:

• the research is permanently closed to enrollment at IU and IU-affiliated sites (collectively “IU sites”),
• all subjects enrolled at IU sites have completed all research-related interventions, including collection of long term follow up data,
• no additional private identifiable information is being collected by the IU investigators, and
• an external statistical center will conduct analysis of all study data about subjects enrolled at IU sites.

Devices

When the principal intent of the medical device (or other product regulated as a device) is to develop information about the product's safety or efficacy, submission of an Investigational Device Exemption application (IDE) is ordinarily required. However, in certain circumstances, the FDA does not require an IDE.

Investigations of devices fall into one of three categories: exempt from IDE requirements, studies of nonsignificant risk (NSR) devices subject to abbreviated IDE requirements, or significant risk (SR) devices subject to full IDE requirements. The assessment of whether a device is exempt from IDE requirements, NSR subject to abbreviated IDE requirements, or SR subject to full IDE requirements is initially made by the investigator and/or the sponsor. The IRB must agree with the assessment based on the proposed use of the device in the research and not on the device alone; however, the FDA has the ultimate decision in determining if a device is IDE exempt, NSR, or SR.

• Exempt from IDE Requirements: The IRB must agree with the justification of exemption; otherwise, the investigator will be required to follow the full or abbreviated IDE requirements. Review the full FDA regulations at 21 CFR 812 for applicability for exemption.
• NSR Device: If the investigator and/or sponsor determines that a device is NSR, the convened IRB considers the explanation of its determination and any other information that may assist in evaluating the risk of the device. The convened IRB may agree or disagree with the assessment of NSR.
• SR Device: In deciding if a device poses a SR, the IRB considers the nature of the harm that may result from use of the device. If the IRB determines that the device is SR, the investigator is notified and the study cannot be approved and/or conducted until the investigator has provided the IRB with documentation of FDA approval of an IDE application, FDA determination that the device is NSR, or FDA IDE exemption determination.

Drugs or Biological Products

If the study involves a drug or biological product used in humans in any way other than in the course of medical practice, an Investigational New Drug application (IND) is required unless certain exemptions apply.  The assessment of whether a drug or biological product requires an IND or is exempt from IND requirements is initially made by the investigator and/or the sponsor.  The IRB must agree with the assessment based on the proposed use of the drug or biological product in the research; however, the FDA has the ultimate decision in determining if the study of the drug or biological product requires an IND. Review the full FDA regulations at 21 CFR 312 for applicability for exemption. If the IRB determines that an IND is needed, the investigator is notified and the study cannot be approved or conducted until the investigator has provided the IRB with documentation of FDA approval of an IND application or FDA IND exemption determination.  Unless a Study May Proceed letter is received from the FDA, the study may not be initiated under an IND until thirty (30) days after submission of the IND application.  If the FDA places the IND on clinical hold, the study may not proceed until the clinical hold is lifted.

Criteria for Approval

Privacy and confidentiality provisions must take into consideration the requirements of privacy standards including the HIPAA Privacy Rule and the Privacy Action of 1974, 5 U.S.C. 552a; VA Claims Confidentiality Statue, 38 U.S.C. 5701; Confidentiality of Drug Abuse, Alcoholism and Alcohol Abuse, Infection with Human Immunodeficiency Virus (HIV), and Sickle Cell Anemia Medical Records, 38 U.S.C. 7332; and Confidentiality of Healthcare Quality Assurance Review Records, 38 U.S.C. 5705.

Scientific Review

The VA Research and Development Committee defers the scientific review for research conducted at or funded by the VA to the IRB.

Amendments

Amendments to VA research involving issues related to biosafety or radiation safety must first be approved by the appropriate committee or subcommittee prior to granting final IRB approval.

Study Expirations

If IRB approval expires, research personnel must immediately submit to the IRB Chair a list of research subjects who could be harmed by stopping study interventions or interactions. The IRB Chair must determine within two (2) business days whether or not such interventions or interactions may continue.

Institutional Review

The facility director is responsible for ensuring that the IRB functions independently. IRB-approved research activities may be disapproved by the IU or VA IO, the Research & Development (R&D) Committee, or Office of Research and Development (ORD).

IRB disapprovals or required modifications to the research cannot be overruled by any other entity.

The Privacy Officer, Information Security Officer, and R&D Committee must provide their final approval before the research can be initiated.

International research must also be approved explicitly in a document signed by the VA medical facility director, except for cooperative studies program activities which must be approved by the CRADO.

The following types of research cannot be approved by a VA facility, IRB or R&D Committee or be performed at VA facilities:

• Classified research involving human participants,
• Research involving the provision of in vitro fertilization services,
• Research in which the focus is either a fetus or human fetal tissue, in-utero or ex-utero.

When conducting human subjects research funded or supported by the DoD, additional regulations and restrictions apply as outlined in Instruction 3216.02.

Non-exempt classified research must be conducted following the requirements of Instruction 3216.02.

Fetal research must be conducted in accordance with, and follow restrictions outlined in US Code Title 42, Chapter 6a, Sub-chapter 3, Part H, 289g.

Research conducted within the Bureau of Prisons must have an adequate research design and contribute to the advancement of knowledge about corrections.

Research funded or otherwise regulated by the DOJ is subject to the Pre-2018 Common Rule Requirements.  As such:

• For new study submissions funded by the DOJ, the grant application is submitted to the IRB and reviewed for congruence with the study protocol; and
• Any non-exempt study funded or otherwise regulated by the DOJ is required to renew annually under the terms of section 3.6 below, even when the study has been determined to be minimal risk.

The IRB may review research which is conducted with human subjects outside of the U.S. When reviewing this research, the IRB ensures that protections equivalent to those in the U.S. are provided to subjects outside the U.S. and consults with experts as needed. Information provided by the researchers within the human subjects application, includes:

• Local laws and regulations regarding human protections,
• Current social, cultural, economic, and/or political considerations which may impact the research or risks to subjects,
• Researchers’ knowledge and experience of the non-U.S. location as it pertains to conduct of the research, as applicable, and
• Documentation of approval from an IRB, ethics committee, government agency or other community group for the non-U.S. location demonstrating adequacy of local context, as applicable. If applicable, documentation of the approval must be provided prior to IU IRB approval.

Use of stem cells in human subjects research is governed by the policy set by the NIH for recipients of NIH research funding.

The day-to-day operations of the IRB are administered and supported by the IU HRPP. No individual responsible for business development at IU or its affiliates may participate in the day-to-day operations of the IRB review process.

The IRB has given HRPP staff the authority to conduct preliminary review of all research submitted to the IRB in order to ensure that it is in an acceptable form for the IRB to review. In addition, HRPP staff ensure required research personnel training is completed at initial review.  

The IU HRPP certifies the review and approval of human subjects research to external funding agencies, as required.

The IRB has delegated authority to HRPP staff to provide guidance to research personnel as to whether an activity requires IRB review; however, HRPP staff may consult with members of the IRB with any questions.

HRPP staff notify the PI and research personnel in writing of IRB actions taken on research.  These notifications may take the form of email notifications, minutes and/or correspondence generated by and maintained in Kuali Protocols which can be downloaded by the researcher for their records.

The study team provides protocol-specific information via the IRB application form and submits the following additional materials, as applicable:

• Data collection instruments
• Recruitment materials
• Informed consent or assent documents, unless a waiver of consent or assent is being requested.
• Protocol document (required for greater than minimal risk research)

The IRB may take appropriate action to protect human subjects when reviewing a research study or submission, including new studies, amendments, renewals, and reportable events.  Appropriate dispositions include:

• Approval: No changes are needed.  The research may proceed.
• Provisional Approval: Specific revisions, stipulated by the convened IRB and requiring simple concurrence by research personnel need to be made.  After revisions have been made, final approval may be granted via the expedited review process.  If provisions are not satisfied as requested by the IRB, the response is returned to the convened IRB for further review. The date of approval is the date the IRB reviewer determines the provisions are satisfied.
• Table: The IRB cannot determine, based on the information provided, that the research meets the criteria for approval and/or revisions are needed that cannot be specifically stipulated by the IRB.  This action can be taken only by the convened IRB, and the response must be reviewed by the convened IRB at a subsequent meeting.
• Disapprove: Significant study concerns exist such that the IRB does not feel the project can be conducted as currently proposed.  Specific reasons for disapproval are included in meeting minutes and communicated to the research personnel in writing.  This action can be taken only by the convened IRB.  Further review of a disapproved submission requires a new submission to the IRB.
• For Reportable Events, accept the item with no further action required (i.e., protocol continues as previously approved and the proposed corrective and preventive action plans, if applicable, are adequate).

Additionally, the IRB may take any of the actions below, as it determines appropriate based on the nature of the submission:

• Refer to or consult with other institutional entities (e.g., department head, University General Counsel, Chief Compliance Officer, or Privacy Officer)
• Restrict use of research data collected
• Audit the research study(ies)
• Modify the research protocol and/or informed consent process/form
• Request notification to or re-consent of past and/or current subjects if the report may relate to their willingness to continue to take part in the study
• Withdraw currently enrolled subjects if it is determined to be in their best interest
• Require additional training of the research personnel and/or research team
• Modify the renewal schedule
• Require increased reporting by research personnel and/or increased monitoring of the research and/or informed consent process
• Restrict privileges of the PI or research personnel to conduct human subjects research

The IRB may, upon the request of research personnel or on its own initiative, reconsider any proposal and reverse its own determination.  Research personnel may appeal a decision made by the IRB by responding in writing to concerns posed by the IRB.  These appeals should be addressed to the HRPP, which will provide this information to the IRB.  The IRB may choose to invite research personnel to a meeting to address the concerns or may reject the appeal based on initial concerns with the research. 

Research studies that are tabled or disapproved by the IRB cannot be resubmitted to a different IRB in an attempt to bypass the original IRB’s decision.

Research that is not being conducted in accordance with the IRB’s requirements or has been associated with unexpected serious harm to participants may also be suspended (temporary cessation of some or all research activities) or terminated (permanent withdraw of IRB approval for all research activities). 

Ancillary Reviews

Some human subjects research requires review by and approval from regulatory offices and committees other than the IRB (ancillary review). Committees not described below are discussed within other sections of this Policy.

• Radiation Safety Committee

Committee review required when human subjects research includes radiation or radioactivity in addition to what is used for standard clinical treatment. Documentation of approval must be provided prior to final IRB approval.

• Institutional Biosafety Committee (IBC)

Committee review required for research involving recombinant or synthetic nucleic acid molecules. Documentation of approval must be provided prior to final IRB approval.

Although research personnel make a preliminary determination about whether research represents minimal risk or greater than minimal risk, the IRB makes the final determination related to risk level and whether the criteria for expedited review procedures are met.  If the IRB does not concur with the study team’s determination, it may request modification to the research or require that the research be submitted for convened IRB review.  If the IRB determines that research appearing in the categories in 2.5 above is more than minimal risk, the IRB must document the rationale. 

Individuals who are appointed as regular or alternate members of an IRB may be designated by the Chair to review research that qualifies for review under expedited procedures. Only experienced IRB members may conduct reviews using the expedited procedure. Experience is determined based on professional or clinical expertise, term of IRB service, and/or specialized knowledge of particular relevance to the specific IRB submission being reviewed. For HRPP staff IRB members, experience is determined by maintaining active Certified IRB Professional (CIP) certification and having completed the expedited review training described in the HRPP staff manual.

Any IRB member who has a conflicting interest in a submission cannot review that submission as an expedited reviewer. Conflicting interests include:

• Participation in the protocol
• PI of the protocol is an immediate family member
• Significant financial interest as defined by the IU Policy on Conflicts of Interest and Commitment
• Certain non-financial interests, including having supervision over the PI of the project or participating in a project that is in direct competition with the project
• Any other real or perceived conflict

In conducting an expedited review, the IRB reviewer may exercise all of the authorities of the convened IRB, except that he/she may not disapprove the research.  Research may only be disapproved by the convened IRB.

Consultants with specific expertise may be utilized to assist in the review of expedited research, when appropriate.  Their comments are documented and forwarded to an IRB member for review and final approval.

A report of research approved via the expedited review procedure is provided periodically to the convened IRB.

Scientific review, which addresses whether the research uses procedures consistent with sound research design that will yield the expected knowledge, is conducted on all human subjects research submitted to the IRB. Scientific review may be conducted by external committees as described below. When scientific review is not conducted by one of these committees, the IRB conducts scientific review as part of determining that the research meets the criteria for IRB approval.

IU Simon Comprehensive Cancer Center (IUSCCC) Scientific Review Committee (SRC)

This committee provides scientific review for prospective cancer-related research utilizing IUSCCC patients or resources. Documentation of the IUSCCC SRC approval must be obtained before IRB approval is granted.

Indiana Clinical and Translational Science Institute (CTSI)

New studies that require review by the convened biomedical IRB and have not undergone a peer-review process must be submitted to the CTSI SRC for scientific review. In addition, research that includes flexible expedited categories 400(b) and/or 700(b) as outlined in Section 2.5 above that has not undergone a peer-review process must be submitted to the CTSI SRC for scientific review. 

• Documentation of CTSI SRC approval must be obtained before IRB approval is granted.
• Peer review may include review of the protocol by an external funder, such as a federal agency or established not-for-profit research foundation, or protocol development by a commercial sponsor, such as a pharmaceutical or medical device company.
• When deemed necessary by an IRB Chair or HRPP Assistant Director, other protocols requiring convened IRB review may be required to obtain CTSI SRC approval prior to IRB approval.

The CTSI-sponsored Project Development Teams (PDTs) assist research personnel in developing ideas/hypotheses into well-designed translational research projects. This goal is accomplished by helping research personnel with protocol development (including scientific review); provision of pilot funding; facilitation of collaboration with other research personnel; and access to certain CTSI Core Resources. Research personnel may request scientific review from the PDTs.

If renewal is required, the current expiration date for the protocol is displayed in Kuali Protocols. The HRPP notifies research personnel of the need to renew a study well in advance of the expiration date.

• Upon notification, research personnel should submit for IRB review the appropriate renewal information, including any necessary protocol attachments.
• Submission for renewal is made through the online Kuali Protocols system. Research personnel complete an IRB application form and, depending on the nature of the research, may also be required to provide additional materials for the IRB's review.

Review of Renewals

The following information must be provided by research personnel at time of renewal and is reviewed by the IRB, as applicable:

• The number of subjects accrued, including a summary of any withdrawal of subjects from the research since the beginning of the study and the reasons for withdrawal, if known
• Summary of minor deviations, research billing errors, and/or minor noncompliance
• If there is no DSMB or DMC, statement whether adverse events occurred studywide in excess of the expected frequency and level of severity as documented in the research protocol, the informed consent document, and investigator’s brochure and, if so, confirmation that the event was promptly reported
• Most recent data safety monitoring results, if applicable
• Any new information that may be relevant in assessing the risks and/or benefits, including literature publications, audit/monitoring findings, results from this or similar studies, and/or interim findings.
• Summary of subject complaints about the conduct of the research, including those resolved by the study team
• The latest version of the IRB-approved protocol and informed consent document(s)
• A brief summary of any promptly reported events and/or amendments to the research approved by the IRB/HRPP since the last IRB review (compiled by the HRPP on the study team's behalf)
• Any proposed modifications to the informed consent document or protocol

When the IRB reviews the current informed consent/assent documents at the time of renewal, it ensures that they are still accurate and complete.  If any significant new findings are identified that may relate to the subject’s willingness to continue participation in the research, the IRB requires that the information be provided to subjects in accordance with regulations. 

The IRB determines whether a protocol requires review in a shorter timeframe than annually and whether additional verification from sources other than the study team are necessary to ensure that no material changes have occurred since the last review based upon the type of research, risks to subjects, and/or previous noncompliance concerns.

The IRB may require renewal for research that would not otherwise require a renewal on a case-by-case basis as it deems appropriate.  If renewal is required, the IRB must document the rationale for such requirement.

Expiration

When renewal is required, there are no provisions for any grace period extending the conduct of the research beyond the expiration date of IRB approval. Additionally, where the convened IRB issues a provisional approval, renewal must occur no more than one year after the date the research was reviewed by the convened IRB. It is the study team's responsibility to ensure that the research is reapproved prior to the study's expiration date.

• If the study team fails to submit a renewal to the IRB or the IRB has not reviewed and approved a research study by 11:59 p.m. on the last date the protocol is approved, research activities must cease, including enrollment of new subjects, interventions on/interactions with current subjects, and analysis of identifiable data.
• However, if the study team is actively pursuing renewal with the IRB and the IRB believes that an overriding safety concern or ethical issue exists such that it is in the best interest of individual subjects for the research to continue, the IRB may permit this while the review process is completed. Enrollment of new subjects, however, cannot occur after the expiration of IRB approval.
• Lapse in IRB approval need not be reported to regulatory agencies as a suspension of IRB approval under HHS regulations.

Research personnel may renew a research study that expired within a reasonable timeframe.  In reviewing this request, the IRB may require modifications to the research prior to reopening and/or the submission of a new research application, as necessary.

If a study team does not submit a continuing review or study closure as outlined in Section 3.8, the HRPP may administratively close the IRB application after making reasonable efforts to contact the study team. Administrative closure of an expired IRB application by the HRPP does not constitute a suspension or termination of IRB approval that requires reporting to regulatory agencies (under 45 CFR 46.113 or 21 CFR 56.108(b)(3)).

Submissions for amendment are made through the online Kuali Protocols system. The study team provides information about the proposed changes and submits revised IRB-approved documents or new materials, as applicable.

Amendments to Expedited Research

Amendments to research previously approved under expedited procedures are reviewed under expedited procedures provided the changes continue to meet the expedited category(ies).  If the proposed changes to the research involve addition of procedures which are not described by the expedited category(ies) or involve greater than minimal risk, the research must be reviewed by the convened IRB.

Amendments to Research Previously Approved by the convened IRB

Pursuant to 45 CFR §46.110(b)(2), minor changes in research previously approved by the convened IRB may be reviewed and approved under an expedited review procedure. Major changes (e.g., those that involve increased risks or discomforts to subjects or decreased potential benefit) are reviewed and approved by the convened IRB. Refer to the IU HRPP website for additional information and examples.

Personnel Changes

Changes in personnel are considered amendments to previously approved research which require prospective IRB approval.

When closing research that is FDA-regulated, subject to VA regulations, and/or greater than minimal risk research, research personnel should provide a final accounting of subject recruitment, withdrawals, adverse events, deviations/noncompliance, and changes to risk/benefit ratio.  The closure is approved by an IRB member via the expedited review process and is reported to a convened IRB.

Minimal risk research which is not FDA-regulated or subject to VA regulations may be closed by an HRPP staff member.

After closure of multi-center research as described in section 2.8 above, identifiable research data may be accessed for the purpose of responding to a database query from an external study sponsor without opening a new research study.  However, if the research was subject to HIPAA, this is only permitted if the subject(s) provided written HIPAA Authorization for participation in the research and the authorization is still valid.  This exception cannot be used to allow collection of new data not previously collected during the research study.

Suspensions of research are typically made at a convened IRB meeting; however, they can also be made on an urgent basis by either an IRB Chair or designee, if necessary. Any suspension or termination includes a statement of the reasons for the IRB's action and is reported promptly to the PI, appropriate institutional officials, and/or the department or agency head.

Suspensions can be lifted only by the convened IRB. If an IRB Chair or designee suspends research, it is reported to the full IRB for consideration and possible action. Termination of research can be made only by the convened IRB. Suspensions and terminations cannot be overturned by Institutional Officials.

When the IRB suspends or terminates a research study, it considers whether the suspension or termination requires that subjects be withdrawn from the study and/or places them at risk of harm.

• When subjects must be withdrawn from a study, the IRB considers the safety, rights, and welfare of subjects and determines necessary termination procedures (e.g., drug tapering, final visit, lab tests, other follow-up, and/or arrangements for continued care).
• If the IRB determines that the suspension or termination will place subjects at risk of harm and/or follow-up of subjects for safety reasons is permitted or required, the IRB determines which subjects are to be notified (e.g., current or past subjects) and the manner in which they are to be notified (e.g., in writing or by telephone). Depending upon the reasons for the suspension or termination and the design of the study, the IRB may require that any of the following individuals be notified of the suspension or termination:
  • All subjects who have been or who are currently enrolled;
  • Only subjects who are currently enrolled and active; or
  • Only subjects who participated in a certain aspect of the study.
• Research personnel may request to attend an IRB meeting to discuss a suspension or termination in order to provide clarification of the issues.

Revisions to 45 CFR 46 (Common Rule) became effective January 21, 2019 (2018 requirements).  

As of July 19, 2018, non-exempt research which met all of the following criteria was transitioned and considered in compliance with and subject to the 2018 Requirements:

• Federally-funded
• Progressed to the point that it involves only data analysis, including analysis of identifiable private information or identifiable biospecimens (i.e., data analysis only)
• Not also subject to FDA, DOJ, or VA regulations

A list of this research is maintained by the HRPP.

Research which was initially approved prior to July 19, 2018, and is federally-funded or otherwise subject to the Common Rule but was not transitioned under the paragraph above may be subjected to the 2018 Requirements at initial review or time of renewal or other submission at the discretion of the institution and/or IRB.  For research transitioned to the 2018 Requirements under this paragraph, the IRB documents the application of the 2018 Requirements at time of approval.

Research which is not federally-funded or otherwise subject to the Common Rule is generally expected to comply with all updates to IU HRPP Policy as quickly as is practicable.  However, research initially approved prior to July 19, 2018, may, with sufficient justification to the IRB, omit one or more of the following elements of informed consent that were first required by the July 19, 2018, IU HRPP Policies:

• One of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:
  • A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or LAR, if this might be a possibility; or
  • A statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.
• A statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit
• For research involving biospecimens, whether the research will (if known) or might include whole genome sequencing (i.e. sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen).