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Introduction and History

Concerns for the welfare of human subjects involved in research began with the Nuremberg Code, which wasdeveloped for the Nuremberg Military Tribunal at the end of World War II as a standard to judge the human experimentation conducted by the Nazis.  The code originates many of the basic principles governing the ethical conduct of research involving human subjects.

A second milestone was the adoption in 1964 by the World Medical Association of the Declaration of Helsinki: Recommendation Guiding Medical Doctors in Biomedical Research Involving Human Subjects.  In 1966 the Public Health Service issued a policy requiring informed consent in research studies.

In 1974, Congress passed the National Research Act, which established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research.  This Act governs the protection of human subjects in research that is supported by the Department of Health and Human Services.  This Act was in response to several abuses in research and ethical violations, most notably the USPHS Tuskegee Syphilis Study.  The Commission's report, the Belmont Report, was published in 1978, with three key principles being respect for persons, beneficence and justice. 

The Belmont Report was implemented by the Department of Health and Human Services as the regulation governing all research involving human subjects supported or conducted by that department.  These rules, referred to as the “Common Rule,” were later adopted by other federal agencies, and all US government funded human subjects research is governed by the Common Rule.  This rule, 45.CFR.46, Protection of Human Subjects, sets forth the following requirements: review by an IRB, informed consent and protections for vulnerable populations.  The Federal Drug Administration has also adopted regulations based upon the National Research Act and the Belmont Report:  21.CFR.50 Protection of Human Subjects, and 21.CFR.56, Institutional Review Boards. In these regulations, IRBs are charged to protect the rights of human subjects from abuse.  It is in accordance with these regulations that the VCOM IRB has been established.  IRB review at VCOM ensures the ethical conduct of the research and that the human subjects involved in the research will be exposed to the least possible risk and greatest possible benefits.

Resources

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Categories of Review

Applications for approval of research involving human subjects may qualify for one of three levels of review: full-board, expedited or exempt.  Before starting an IRB application, investigators must identify the appropriate review type.  Investigators are encouraged to contact the IRB Coordinator to discuss what review type their protocol falls under.

Exempt Review

This type of research represents no more than minimal risks to participants and does not involve special populations.  The purpose of this review is to determine if the research is in keeping with the exempt categories as defined by federal regulation and thus exempt from expedited or full-board review.  This type of research still requires submission of the protocol to the IRB Coordinator and Chair for review and approval of the exemption.  The Chair and a designated member of the IRB are authorized to determine if the research qualifies for exemption based upon the federal regulations.  Normally, informed consent is not required for exempt research.  If the IRB Chair determines that a signed informed consent form is required, the request will be upgraded to expedited or full-board review.  Research that falls into one of the categories below may be considered exempt:

  • Research conducted in established or commonly accepted educational settings, involving normal educational 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.
  • 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 subjects can be identified, directly or through identifiers linked to the subjects; and (ii) any disclosure of the human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability, or reputation.
  • 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 the above paragraph, if: (i) The human subjects 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.
  • 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.
  • Research and demonstration projects which are conducted by or subject to the approval of department or 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.
  • Taste and food quality evaluation and consumer acceptance studies, (i) if wholesome foods without additives are consumed or (ii) 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 Food and Drug Administration or approved by the Environmental Protection Agency or the Food Safety and Inspection Service of the U.S. Department of Agriculture.

Information taken from: 45.CFR.46.101(b)(1-6).

Only members of the IRB may determine that a study is exempt from expedited or full-board review.  Once a study is deemed exempt, it will not be required to undergo further review, such as continuing review, unless the protocol changes in such a way that it no longer falls under any of the exemption categories described above.

Expedited Review

In circumstances where there is no more than minimal risk, federal regulations permit the IRB to conduct expedited review.  The VCOM IRB may also use the expedited review procedure to review minor changes in a previously approved research during the period for which approval is authorized (no more than one year). 

Studies involving children can be approved under expedited review.  The categories for expedited review are the same as in adult studies; however, blood collection limits differ.  Research involving collection of protected health information (PHI) that is approved by both the parent and child with appropriate consent and assent forms can use expedited review. 

The categories for expedited review are:

  • Clinical studies of drugs and medical devices when:  (a) Research on drugs for which an investigational new drug application (21 CFR Part 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 (b) Research on medical devices for which (i) an investigational device exemption application (21 CFR Part 812) is not required; or (ii) the medical device is cleared/approved for marketing and the medical device is being used in accordance with its cleared/approved labeling.
  • 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 (Note, 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 (b) 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 (Note, 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).
  • 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 time of exfoliation or if routine patient care indicates a need for extraction; (c) permanent teeth if routine patient care indicates a need for extraction; (d) excreta and external secretions (including sweat); (e) 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; (f) placenta removed at delivery; (g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; (h) 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; (i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; (j) sputum collected after saline mist nebulization.
  • 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: (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, electroencephalography, thermography, detection of naturally occurring radioactivity, electroretinography, ultrasound, diagnostic 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.
  • 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: Some research in this category may be exempt from the HHS regulations for the protection of human subjects.  This listing refers only to research that is not exempt.)
  • Collection of data from voice, video, digital, or image recordings made for research purposes.
  • 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: Some research in this category may be exempt from the HHS regulations. This listing refers only to research that is not exempt.)

Information taken from: OHRP Categories of Research, Expedited Review Procedure

These expedited categories represent minimal requirements of review, and the VCOM IRB may call for a more stringent review of any study.  Expedited Review may be carried out by the IRB Chair and a member of the IRB or by two IRB members designated by the Chair. When conducting an Expedited Review, IRB members may exercise all of the authorities of the IRB, except that the reviewer(s) may not disapprove the research.  A research activity may be disapproved only after a full IRB review has been conducted.  All IRB members must be advised of research proposals that have been approved using expedited procedures at the next regularly scheduled meeting.

Full-Board Review

Full-board review by the entire IRB committee is reserved for studies that have potential risk to human subjects.  All research that does not meet the criteria for exempt or expedited review will be reviewed by the full Board at a regularly convened meeting. For the research to be approved, it must receive the approval of a majority of those members present at the meeting. If the IRB Chair has any concerns about any aspect of the application, he may request full IRB review of any application even though it may otherwise qualify for exemption or expedited review.  Potential risks to human subjects that would warrant full-board review include, but are not limited to:

  • Research that involves the administration of drugs or other substances to subjects where an IND/IDE are required.
  • Research that materially affects the pregnancy of a woman or the health/well-being of fetuses in utero.
  • Research involving subjects with life-threatening physical conditions.
  • Research involving physically intrusive procedures.
  • Research that previous experience (by the particular investigator or other investigators) has been shown to create a potential of risk to subjects.
  • Research that may result in a significant level of psychological or physical stress.
  • Research that potentially could put the subject at risk for legal or civil liability or invade a subject's privacy in regard to sensitive aspects of his/her behavior (e.g., illegal conduct, drug use, sexual behavior, alcohol use) when there is a possibility that the subject could be identified.
  • Research involving prisoners.
  • Research that places protected populations (such as children, mentally ill individuals, patients with medical disorders) at more than minimal risk.
  • Research involving waivers of any HIPAA regulations.
  • Research that is not conducted for the primary benefit of the subjects.
  • Deception or procedures that are not known to the subject (e.g., the subject will not be fully informed about study objectives).

Investigators with applications under full-board review may be present at the IRB meeting covering their protocol in order to answer questions posed by IRB members.  Attendance at these meetings is optional, unless otherwise indicated by the IRB Chair, and should be scheduled with the IRB Coordinator at least a week prior to the designated meeting.

Continuing Review

IRB approvals may be given for periods of time not exceeding 12 months; however, the approval period may be shorter at the discretion of the IRB. If an approved project is not completed in the time-period specified in the original approval, re-approval is required. Re-approval requires the same process as the original approval.

Thirty days prior to the next scheduled review period, the IRB Coordinator will send the investigator a reminder letter and a Continuing Review / Final Report Form that must be completed and returned to the Coordinator at least one week before the next IRB meeting that occurs before the continuing review date. Should a lapse in approval occur due to untimely submission of the continuing review, any data collected during this time may not be used for publication. The regulations make no provision for any grace period extending the conduct of the research beyond the expired date of IRB approval.

If the project was originally granted expedited approval, the IRB Chair may give a re-approval if there have not been adverse incidents and if the level of risk has not changed. If the original request was approved by the full IRB, it must go back to the full IRB for re-approval unless the following conditions apply (in which case the IRB Chair may give expedited approval):

  • Where: (i) the research is permanently closed to 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
  • Where no subjects have been enrolled and no additional risks have been identified; or
  • Where the remaining research activities are limited to data analysis.

The IRB Chair may conduct on-site observation of any approved research project. This on-site visit may include any or all of the research processes involving human subjects. If significant deviations from the approved research protocol or informed consent procedures are found or if the risks to the participating subjects are greater than indicated in the approval documents, the IRB Chair may suspend the IRB approval until a full investigation can be completed.

Information taken from:  45.CFR.46.109(e).

Resources

OHRP Human Subjects Decision Charts provide graphic assistance as a guide for investigators.

Definition of Research

Exemptions

Expedited Review

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Informed Consent

Voluntary participation and control of the information about the human subject by the participant is imperative to the appropriate conduct of research. Participants must be fully informed about the research, the risks and benefits, and they must agree to participate in writing. This written agreement to participate voluntarily after having been fully informed is referred to as and signifies Informed Consent.

The typical expectation is that all participants will participate in the informed consent process, including signing the informed consent document. The informed consent document provides a complete description of the study that is clear enough for the individual to decide whether he or she wants to participate. 

Informed consent is a process: the process of communication between the potential participant and the principal investigator or other qualified member of the research team wherein the research study is explained to the participant so that the participant can make an informed decision about whether or not to partake in the research study.  This process involves having a conversation with the prospective participant to ensure that the participant understands the research study and the reasons why the study is being conducted as well as the risks and benefits of the research. The conversation must allow the participant sufficient time to ask questions and to consider whether to participate in the study.  The informed consent process is most often documented by the use of an IRB approved and validated informed consent form.  The individual obtaining consent must be trained in human subject protection, have an in-depth knowledge about the research study and be able to answer all questions posed by the participant.  It is important to note that the consent document must not serve as a substitution for discussion.

Consent must be obtained prior to any involvement of the participant in a study.  All consent forms must include instructions for the participants as to whom to contact regarding research related questions, research related injuries (if applicable) and how to contact the VCOM IRB regarding their rights as a research participant. 

General Requirements for Informed Consent:  Federal guidelines mandate certain specific elements that must appear in the consent form (45.CFR.46.116 and 21.CFR.50.25). Per regulations, the following elements must be included, and the following information must be provided to each participant:

Element Information to be Provided
Research purpose and study information
  • A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed and identification of any procedures which are experimental.
Reasonable risks
  • A description of any reasonably foreseeable risks or discomforts to the subject.
    Note that risks may be physical, psychological or social.
Benefits
  • A description of any benefits to the subject or to others which may reasonably be expected from the research.
    Note that compensation is not a benefit for participation in research.  Provide separate statements for the benefits to the subject and the benefits to others.
Alternative procedures
  • A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
Confidentiality
  • A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained.
    Note that in some research, the data is recorded in such a manner that the subjects can be identified either by name or through other identifiers such as a code. If this is applicable, include a statement regarding the researcher's ability to link the data to the identity of the subject and a description of the procedures to maintain the confidentiality of person-identifiable data. Do not include the following statement: “All person identifiable data will be coded so that you cannot be identified.”
Compensation for injury
  • For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
Contact information
  • An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.
Voluntary participation
  • A statement that participation is voluntary, refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

In addition to the above, add the sentence: “This project has been reviewed and approved according to the Edward Via College of Osteopathic Medicine’s procedures governing your participation in this research.”

When appropriate, additional elements and information may also be required to be provided to the participants in the informed consent documents.

Element Information to be Provided
Unforeseeable risks
  • A statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable;
Participation termination
  • Anticipated circumstances under which the subject's participation may be terminated by the investigator without regard to the subject's consent;
Additional costs
  • Any additional costs to the subject that may result from participation in the research;
Consequences of withdrawal
  • The consequences of a subject's decision to withdraw from the research and procedures for orderly termination of participation by the subject;
Significant new findings
  • A statement that significant new findings developed during the course of the research which may relate to the subject's willingness to continue participation will be provided to the subject; and
Number of subjects
  • The approximate number of subjects involved in the study.
ClinicalTrials.gov
  • Language must be included in the consent documents for applicable studies that states the study has been registered at http://www.ClinicalTrials.gov.
    Per 21 CFR 50.25(c), the following language must be included: “A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”

Waiver of Informed Consent Process: Under certain circumstances, the IRB may approve a consent procedure which does not include, or which alters, some or all of the elements of informed consent, or the IRB may waive the requirements to obtain informed consent.  Per guidelines, 45.CFR.46.116(d) the following conditions must all be met:

  • The research involves no more than minimal risk to the subjects;
  • The waiver or alteration will not adversely affect the rights and welfare of the subjects;
  • The research could not practicably be conducted without the waiver or alteration; and
  • Whenever appropriate, the subjects will be provided with additional pertinent information after participation.

If an investigator believes his or her research meets the conditions above, he or she must provide justification to the IRB.  This information will be reviewed by committee members.  Justification includes an explanation of the protocol in support of the waiver request and identification and explanation of the elements of consent that will be altered or omitted.  The investigator must explain the risks involved in the proposed research and why the research presents no more than minimal risk to the participants.  In addition, the investigator must describe how the waiver or alteration of consent will not adversely affect the rights and the welfare of the participants. If appropriate, the investigator must also define a plan to provide the participants with pertinent information after participation. And finally, the investigator must explain why the research could not practically be conducted without the waiver or alteration of consent.

Waiver of Informed Consent Documentation:  In some circumstances, the IRB may waive the requirement for the investigator to obtain a signed consent form for some or all of the participants.  This can happen if the IRB finds:

  • That the only record linking the participant and the research would be the consent document and the principal risk would be potential harm resulting from a breach of confidentiality, or
  • That the research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.  

If an investigator believes his or her research meets the conditions for waiver of informed consent documentation, he or she must explain how the consent document is the only record linking the participant to the research and how the principal risk to the participant is the potential harm from a breach of confidentiality. 

In cases in which the documentation requirement is waived, the investigator must ask each participant whether or not he or she wants documentation linking him or her with the research.  In addition, the IRB may require the investigator to provide subjects with a written statement regarding the research.

In all cases the IRB is required to find and document justification for any alteration to the requirements of consent.  For both a request for waiver of the process or waiver of documentation, the investigator must complete Form F: Application for Waiver or Alteration of Informed Consent Procedures and submit to the IRB as part of the IRB application packet.

See the Sample Consent Outline on the IRB forms website.  The Informed Consent Checklist can assist with developing procedures.

Assent:  In the Commonwealth of Virginia only individuals who are 18 years old or older, may legally consent to participate in research.  (In addition, this legal authority may be withheld from some individuals with limited decision-making or cognitive ability.)  Individuals who do not have the authority to consent to participate in research must still provide their assent, which may be in writing, oral or in some circumstances, by action or behavior (very young children).  Assent is a knowledgeable agreement to participate in the project.  It differs from consent, which is recognized as being granted from an individual with the legal authority to do so. For children or cognitively impaired adults to participate as research subjects, parental or legal authorized representative permission (informed consent) and the child's assent is required.

Children cannot legally give consent; however, they can provide assent.  Suitable provisions should be made for soliciting the independent, assent from children or cognitively impaired persons who are capable of a knowledgeable agreement.  In cases where assent is obtained from a child or cognitively impaired participant, permission must also be obtained from parents or legally authorized representatives.  In accordance with the ethical principal of respect for persons, if the person from whom assent is sought refuses, that person should not be enrolled, even if the parents or legally authorized representatives give permission.  Alternatively, if the person from whom assent is sought agrees to participate, the person may not be enrolled if the parents or legally authorized representatives do not give permission. 

In rare circumstances, depending on the nature of the study and the age and circumstances of the child or cognitively impaired person, the IRB may waive the requirement for permission from parents or legally authorized representatives (as an example, an emancipated minor).

The IRB may require that a separate assent statement is necessary.  The IRB will determine whether the investigator has adequate provisions to solicit assent, and if the children are capable of providing it. The researcher must inform the IRB how the affirmative assent of the child will be documented (by signature on assent form, documented by the researcher or other). Both the assent form and the assent discussion with the participant should be in an age-appropriate language especially tailored for participant and should include the following:

  • Explanation of why the study is being conducted;
  • Description of what will happen and for how long or how often;
  • Inclusion of section stating it is up to the child/individual to participate and that it is okay to say no;
  • Explanation of if it will hurt and for how long and how often;
  • Explanation of what the child's/individual's other choices are;
  • Description of any good things that might happen;
  • Inclusion of information on whether there is any compensation for participating; and,
  • Time for child/individual to ask questions.

The assent form should be limited to one page.  Illustrations might be helpful and larger type makes it easier for some individuals to read.  An oral assent (omission of signature) may also be considered for younger children.

A parental permission form will also be required if an assent form is deemed appropriate.

See the Assent Form Template on the IRB Forms website.

Other Required Elements:  The VCOM IRB also requires the following elements to be included in the consent process, where appropriate:

  • Electronic Collection of Data:  Research involving the electronic collection of data (e.g. by e-mail or an internet web site) must also include the statement: "While it is understood that no computer transmission can be perfectly secure, reasonable efforts will be made to protect the confidentiality of your transmission.”
  • Research Involving Videotaping/Audiotaping:  Research involving videotaping and/or audio-taping must include a description of when the taping will take place, the information being sought from the tapes, how the tapes will be kept secure, who will have access to the tapes, and if applicable, when the tapes will be destroyed.
  • Mandatory Reporting Requirements Regarding Suicide, Child or Elder Abuse and Intent to Kill or Cause Serious Bodily Harm to Another Person:  In some research, the participants' responses could indicate intent to commit suicide, intent to kill or cause serious bodily harm to another person, and/or knowledge of past, current, or future unreported child abuse or elder abuse. Mandatory reporting requirements under the Virginia Code of Law must be included in the informed consent form.

Other Resources: The following links are to federal resources that will aid in the understanding of the consenting process and in the development of an informed consent document.

OHRP Human Subjects Decision Chart 10: Can Informed Consent Be Waived or Consent Elements be Altered?  These charts provide graphic assistance as a guide for investigators.
OHRP Human Subjects Decision Chart 11: Can Documentation of Informed Consent Be Waived? 
OHRP Policy and Guidance, Informed Consent: These guidance materials include documents that address autonomy and consent issues.
OHRP Informed Consent FAQs (PDF file available here)
NIH’s website on Informed Consent FAQs:  These questions focus on waivers, incidental findings and resolving concerns.
FDA Guide to Informed Consent Information Sheet: Covers general requirements and FDA approval for studies, when required.
NIMH’s video, The Elements of a Successful Informed Consent: Will open a YouTube video (24 minutes).
OHRP video, General Informed Consent Requirements:  YouTube video (18 minutes).

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Special Populations

Vulnerable subjects in research are individuals who lack the capacity to provide informed consent or whose willingness to participate in research may be unduly influenced by others. 
Federal regulations require that IRBs give special consideration to protecting the welfare of particularly vulnerable subjects such as:

  • Children
  • Prisoners
  • Pregnant women, fetuses, neonates or human in vitro fertilization

In addition, other groups including mentally disabled persons, economically or educationally disadvantaged persons and students, employees and others in subordinate positions, may also be considered vulnerable populations and call for special consideration.  If the IRB identifies such circumstances, additional protections for safeguarding those subjects may be required.

Information on special populations as regulated in 45.CFR.46 subparts B, C and D is available here.  In addition, information on other special populations and safeguards for investigators to consider is also available.

Vulnerable subjects in research are individuals who lack the capacity to provide informed consent or whose willingness to participate in research may be unduly influenced by others.  These individuals may be especially susceptible to coercion or undue influence.

When research involves vulnerable subjects, the investigator must provide appropriate additional safeguards to protect their wellbeing. Because they are sometimes proposed as research subjects on account of their vulnerability, investigators may be asked to explain the appropriateness of involving them in the research. The investigator is required to indicate the involvement of potentially vulnerable populations to the IRB in the application and provide a description of safeguards to protect the rights and welfare of the vulnerable subjects. The IRB may require further protections for safeguarding those subjects as a condition of approval.  Research involving any vulnerable population must have approval from the full IRB (complete IRB Form A), unless it qualifies for expedited review (IRB Form B).

Although federal regulations only identify special protections for specific populations, the IRB will evaluate each protocol for circumstances that may place subjects in vulnerable situations that call for special consideration. If the IRB identifies such circumstances, additional protections for safeguarding those subjects may be required as a condition of approval.

Generally, approval for research projects involving vulnerable populations/groups may be considered if one of the following conditions is met:

  • The research does not involve greater than minimal risk to the subject;
  • The research is likely to benefit the subject directly, even though the risks are considered to be more than minimal; or
  • The research involves greater than minimal risk with no prospect of direct benefit to individual subjects but is likely to yield generalizable knowledge about the subject’s disorder or condition.

If a proposed protocol will involve children, prisoners, pregnant women and fetuses or neonates, federal law dictates requirements on the selection of subjects, risk assessment, obtaining consent, and so forth. These additional protections are located in the following subparts to 45.CFR.46

  • Subpart B:  Additional protections for pregnant women, human fetuses and neonates involved in research
  • Subpart C:  Additional protections pertaining to biomedical and behavioral research involving prisoners in research
  • Subpart D:  Additional protections for children involved as subjects in research

Investigators will need to familiarize themselves with these additional protections and ensure an adequate plan of protection in their protocol should they involve vulnerable populations in their research.

Children

Children are defined as minors in the jurisdiction in which they reside. The Commonwealth of Virginia defines anyone under the age of 18 as a minor. For children to participate as research subjects, parental/guardian informed consent (permission) and the child's written informed consent (assent) are both required. In general, one or both parents or a guardian must be provided with the information ordinarily required for informed consent, so that they may decide whether to allow the child to participate, and children capable of assent must also express their willingness to participate. The age at which a child may give informed consent is a determination of the IRB. The child's informed consent or assent must be written in language that he/she could be reasonably expected to understand. Subpart D allows for various conditions and waivers of parental permission and child assent, depending on the nature of the research activity and the maturity of the child.

The VCOM IRB adheres to the regulatory requirements for research with children, as outlined in 45.CFR.46 Subpart D. The categories for approval of research involving children are based on the degree of risk and benefit to individual subjects as follows:

  • Research that does not involve greater than minimal risk:  This may be approved if the IRB finds that adequate provisions are made for soliciting the assent of the child and the permission of his/her parent(s) or guardian.
  • Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual participants: This may be approved if the IRB finds that:
    • The risk is justified by the anticipated benefit to the participant;
    • The relationship of anticipated benefit to risk is at least as favorable as that presented by available alternative approaches; and
    • Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians.
  • Research involving greater than minimal risk with no prospect of direct benefit to individual participants, but likely to yield generalizable knowledge about the participant's disorder or condition:  This may be approved if the IRB finds that:
    • The risk represents a minor increase over minimal risk;
    • The intervention or procedure presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;
    • The intervention or procedure is likely to yield generalizable knowledge about the participant's disorder or condition which is of vital importance for the understanding, prevention, or alleviation of the participant's disorder or condition; and
    • Adequate provisions are made for soliciting permission of the parents or guardians and assent of the child.
  • Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children:  This may be approved if the IRB finds that:
    • The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; or
    • When the study is funded by the DHHS, the DHHS Secretary has to determine either that the research in fact satisfies the conditions described in the preceding three bullets; or
    • The research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and
    • The research will be conducted in accordance with sound ethical principles; and
    • Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians (see requirements for these provisions in 45.CFR.46.408).

Research involving children who are wards of the state or any other agency, institution, or entity can be included in research under bullets 3 and 4 only if that research is:

  • Related to their status as wards, or
  • Conducted in schools, camps, hospitals, institutions, or similar setting in which the majority of children involved as participants are not wards.

In addition, Subpart D reduces the scope of the exemption regarding research activities involving education tests, survey or interview procedures, or observation of public behavior, if the subjects are children (45 CFR 46.101(b)(2)). The exemption of research activities involving survey and interview procedures is eliminated. The exemption is also narrowed for research involving observation of public behavior, by eliminating the exemption of any research involving observation of public behavior if the investigator will participate in the activities being observed.

Research conducted in schools must be approved by the school or the school system. This is typically done by the classroom teacher and the principal or an assistant superintendent. Approval by an individual teacher is insufficient. School approval should accompany the approval request to the IRB.

Some persons under the age of 18 may qualify as emancipated minors. In 45.CFR.46 emancipation of a minor is defined as: “A legal status conferred upon persons who have not yet attained the age of legal competency as defined by state law (for such purposes as consenting to medical care), but who are entitled to treatment as if they had by virtue of assuming adult responsibilities such as being self-supporting and not living at home, marriage, or procreation.”

Prisoners

Subpart C of 45.CFR.46 requires modification of IRB membership for review of research involving prisoners. Specifically, at least one member of the IRB must be a prisoner or a prisoner representative with appropriate background and experience to serve in that capacity. An investigator contemplating research using prisoners as subjects should consult Subpart C and the IRB Chair for specific requirements.

Subpart C defines a prisoner as any individual who is involuntarily confined or detained in a penal institution.  Federal regulations do not differentiate between detention, jail or prison. People incarcerated in any of these places are considered prisoners. This includes individuals who are:

  • Sentenced under a criminal or civil statue, or
  • Detained in other facilities by virtue of statues or commitment procedures which provide alternatives to criminal prosecution or incarceration in a penal institution, or
  • Detained pending arraignment, trial or sentencing

No research that involves prisoners will be considered exempt.  Per regulation (45.CFR.46.101 Footnote 1), the exemptions that generally apply to certain types of research involving human subjects do not apply to research involving prisoners.

Biomedical or behavioral research may involve prisoners as subjects only if the proposed research involves solely the following:

  • Study of the possible causes, effects and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
  • Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
  • Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction and sexual assaults); or
  • Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject.

In any of the above scenarios, approval can only be given after VCOM has certified to Secretary of DHHS that the IRB has approved the research under Subpart C and the Secretary judges agrees with the decision.

The regulations that apply to prisoner enrollment in human subject research studies also apply to participants already enrolled in a study who become incarcerated.  If an enrolled participant becomes a prisoner and the investigator wishes the participant to continue in the project, the investigator must notify the IRB immediately, cease all research interactions involving the individual and begin the process to amend the protocol to include the enrollment of prisoners.

Pregnant Women, Fetuses and Neonates

Research involving pregnant women, fetuses and human in vitro fertilization are subject to specific federal regulations that guide IRB deliberations on such studies (Subpart B).  Research studies involving the participation of pregnant women or fetuses can be approved by the IRB if the following requirements of federal regulations are met:

  • Preclinical studies (including studies on pregnant animals) and clinical studies (including studies on non-pregnant women) have been conducted and provide data for assessing potential risks to pregnant women and fetuses.
  • The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means.
  • Any risk is the least possible for achieving the objectives of the research.
  • Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate.
  • For children who are pregnant, assent and permission are obtained in accord with federal regulations regarding children in research.
  • No inducements, monetary or otherwise, will be offered to terminate a pregnancy.
  • Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy.
  • Individuals engaged in the research will have no part in determining the viability of a neonate.

There are specific regulations governing research involving fetuses, whether viable, non-viable or uncertain viability.  These regulations fall under Subpart B, specifically, 45.CFR.46.205.

Consenting requirements dictate that the mother's consent is required when the research holds:

  • The prospect of direct benefit to the pregnant woman , or
  • The prospect of a direct benefit both to the pregnant woman and the fetus , or
  • No prospect of benefit for the woman nor the fetus but risk to the fetus is not greater than minimal, and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means.

Consent from the mother and father is required (unless the father is absent, incompetent, unknown or the pregnancy resulted from rape/incest) when the research holds out the prospect of direct benefit solely to the fetus.

An investigator contemplating using pregnant women, fetuses or human in vitrofertilization must consult Subpart B and the IRB Chair for specific requirements. Information is also available in the VCOM IRB Policies and Procedures document, available in the VCOM Institutional Policy and Procedure Handbook.

Other Populations Requiring Special Consideration:  While there are currently no specific federal regulations that address the needs of these populations, the VCOM IRB will carefully consider projects that involve any of the following groups:

  • Mentally disabled persons;
  • Economically or educationally disadvantaged persons; and
  • Students, employees and others in subordinate positions.

Every project reviewed by the VCOM IRB is evaluated for circumstances that may place participants in vulnerable situations.  When the IRB deems a group as being vulnerable in a particular research project, the committee will consider whether the protocol provides adequate protections and may require additional protections as a condition of approval.

Mentally disabled persons are those who have a diminished capability for judgment and reasoning due to developmental, psychiatric, organic or other disorders that affect cognitive functions. The VCOM IRB holds that research involving mentally disable persons should not be done if:

  • The research questions could be answered by involving capable persons or
  • More than minimal risk is involved (unless the research holds out direct benefit to the subject)

Furthermore, research that must involve this population must include safeguards that show decision making capacities will be tested and documented in the study.  The investigator must provide thorough justification on why such a population is the only appropriate one for the research, and must detail how adequate informed consent will be obtained.

The Department of Health and Human Services has available FAQs on involving mentally disabled persons in research: 

Economically or educationally disadvantaged persons may also require special protections in a research environment.  When such groups are targeted specifically as research subjects, the IRB will ensure adequate safeguards are in place to protect such individuals.

  • For research involving economically disadvantaged participants, care must be taken to assure that any financial incentives offered do not represent the only grounds for the individual’s participation in the research protocol.
  • Financial incentives should also not be used to encourage participants to assume risks that they would not ordinarily incur. 

The consent form for research involving educationally disadvantaged participants must be written in language appropriate to the participant. In some cases, the investigator must discuss orally every aspect of the study with the participant to insure participant understanding.

The Department of Health and Human Services FAQs include insights into situations involving economically or educationally disadvantaged persons:

Students, employees and others in subordinate positions can feel unduly influenced to participate. In many studies, students are recruited as participants; however, investigators should be aware of possible coercion when involving students in their research.  If students believe their participation (or lack of) will be made known to someone involved in his or her academic status, the student may perceive coercion. This also holds true for employees and others at VCOM who may be in subordinate positions. 

If an investigator is planning to involve students or employees in a research study, the potential problems of coercion and undue influence must be addressed in the application.  In particular, activities that involve students who attend a class the investigator teaches or employees who report directly to the investigator must be disclosed and explained.  The IRB will consider whether the autonomy and confidentiality of these individuals are protected.  Such considerations include:

  • Incentives for participation do not present undue influence;
  • Participants have the ability to decline participation;
  • Confidentiality is maintained for self-disclosures of a personal nature;
  • If course credit is given for participation, alternatives no more burdensome than the research participation are available for receiving equal credit.

Department of Health and Human Services FAQs raise questions for consideration when involving students and others in subordinate roles in research: 

Other Resources

The following links are to federal resources that describe the requirements dictating vulnerable subject participation in research and the steps investigators should take to ensure all safeguards are met.

OHRP video, Research Involving Vulnerable Populations:  YouTube video (28 minutes).
OHRP’s guidance: Special Protections for Children as Research Subjects 
ORRP FAQs on Research with Children 
OHRP FAQs on Prisoner Research

NIH guidance on Research Involving Vulnerable Populations

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Additional Training

Frequently, programs are presented at area institutions that are aimed at research involving human subjects, confidentiality and other ethical concerns for researchers. The IRB Coordinator will inform deans and discipline chairs of upcoming events, so this information can be disseminated to faculty and students at VCOM who may be interested in attending.

If you have any questions on training opportunities, please contact the IRB Coordinator.