D. Special Considerations in Institutional Review Board (IRB) Review

**[Chapter 12]{.underline}: Behavioral and Social Sciences Research**

Behavioral and Social Sciences research often involves surveys,
observational studies, personal interviews, or experimental designs
involving exposure to some type of stimulus or intervention. This
section discusses when exemption and expedited review are appropriate
for this type of research.

a.  **Social and Psychological Harms.** When evaluating behavioral and
    social science research, IRBs should carefully examine the research
    to determine the probability of risk of harm to subjects.

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(1) The IRB should consider the potential for participants to experience
    stress, anxiety, guilt, or trauma that can result in genuine
    psychological harm.

(2) The IRB should also consider the risks of criminal or civil
    liability or other risks that can result in serious social harms,
    such as damage to financial standing, employability, insurability,
    or reputation; stigmatization; and damage to social or family
    relationships.

(3) If information is being collected on living individuals other than
    the primary "target" subjects the IRB should consider the risk of
    harm to those "non-target" individuals, as well.

> To mitigate such risks, IRBs should review the proposal for
> appropriate preventive protections and debriefings, adequate
> disclosure of risks in the informed consent information, and
> mechanisms to protect the confidentiality and privacy of persons
> participating in or affected by the research.

b.  **Privacy and Confidentiality Concerns.** The use of confidential
    information is an essential element of much social and behavioral
    research.

    1.  It is important to ensure that the methods used to identify
        potential research subjects or to gather information about
        subjects do not invade the privacy of the individuals. In
        general identifiable information may not be obtained from
        private (non-public) records without the approval of the IRB and
        the informed consent of the subject. This is the case even for
        activities intended to identify potential subjects who will
        later be approached to participate in research. However, there
        are circumstances that are exempt from the regulations, and
        circumstances in which the IRB may approve a waiver of the usual
        informed consent requirements. These have been discussed
        previously in Chapters 9 and 11, and will also be discussed
        briefly in following sections of this chapter.

    2.  It is also important to ensure that adequate measures are taken
        to protect individually identifiable private information once it
        has been collected to prevent a breach of confidentiality that
        could lead to a loss of privacy and potentially harm subjects.

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c.  **Safeguarding Confidentiality.** When information linked to
    individuals will be recorded as part of the research design, IRBs
    should ensure that adequate precautions shall be taken to safeguard
    the confidentiality of the information. The more sensitive the data
    being collected, the more important it is for the researcher and the
    IRB to be familiar with techniques for protecting confidentiality.

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(1) IRBs that review research in which the confidentiality of data is a
    serious issue should have at least one member (or consultant)
    familiar with the strengths and weaknesses of the different
    mechanisms available.

(2) IRBs that review survey and interview research should be
    particularly aware of the regulatory provision at 38 CFR
    16.117(c)(1) for waiving documentation of consent when a signed
    consent form constitutes the only link between the research and the
    subjects and would itself be a risk to the subjects (Chapter 10).

(3) Among the available methods for ensuring confidentiality are coding
    of records, statistical techniques, and physical or computerized
    methods for maintaining the security of stored data.

(4) Department of Veterans Affairs (VA) regulations at 38 CFR
    16.116(a)(5), Food and Drug Administration (FDA) regulations, and
    the Common Rule require that subjects be informed of the extent to
    which confidentiality of research records will be maintained.

(5) IRBs should be aware that Federal officials have the right to
    inspect and copy research records, including consent forms and
    individual medical records, to ensure compliance with the rules and
    standards of their programs. FDA requires that information regarding
    this authority be included on the consent information for all
    research that it regulates. Identifiable information obtained by
    Federal officials during such inspections is protected by the
    provisions of the Privacy Act of 1974.

(6) IRBs may require that an investigator obtain a Department of Health
    and Human Services (DHHS) Certificate of Confidentiality (CoC). The
    CoC protects against the involuntary release of sensitive
    information about individual subjects for use in Federal, state, or
    local civil, criminal, administrative, legislative, or other legal
    proceedings. CoCs are discussed in Chapter 10.

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d.  **Exempt Research.** Some social and behavioral research is exempt
    from the requirements of the VA regulations (38 CFR 16.101(b)) and
    the Common Rule. However, appropriate application of these
    exemptions requires a relatively sophisticated level of expertise
    and should not be left to individual investigators. The
    institutional decision maker (the R&D Committee or designee) must
    elicit enough information from the investigator to ascertain whether
    the claimed exemption really applies.

> All exemptions claimed for research conducted in this facility or by
> employees or agents of this facility must be determined by the VA
> Medical Center (VAMC) Research and Development (R&D) Committee and
> approved by the IRB. (See M-3, Part 1, Chapter 9) The following
> exemptions are particularly applicable to social and behavioral
> research. These exemptions do not apply to FDA regulated research.
> *([Note]{.underline}: Some VAMCs may elect to have the IRB review
> research that would be exempt under the regulations. This decision
> should appear in the IRB standard operating procedure (SOP).)*

e.  **Exempt Research in Educational Settings.** Research conducted in
    established or commonly accepted educational settings that involves
    normal educational practices is exempt from VA regulations and the
    Common Rule in accordance with 38 CFR 16.101(b)(1).

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(1) This exemption does not apply if the setting is not commonly
    recognized as an educational one, or if other than normal
    educational practices are employed.

(2) Even if the research is exempt, the investigator has an ethical
    obligation to ensure that students' rights and welfare are
    respected.

(3) When educational institutions become engaged in the actual conduct
    of research, they are required to file an Assurance in accordance
    with VA regulations at 38 CFR 16.103(a) and the Common Rule. OHRP
    guidance on the definition of engagement of institutions in research
    is contained in Appendix VII.

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f.  **Exempt Research Using Educational Tests (Cognitive, Diagnostic,
    Aptitude, and Achievement Tests), Survey Procedures, Interview
    Procedures, or the Observation of Public Behavior.** Research
    involving the use of educational tests (cognitive, diagnostic,
    aptitude, achievement), survey procedures, interview procedures, or
    the observation of public behavior is ordinarily exempt under VA
    regulations at 38 CFR 16.101(b)(2).

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(1) When the subjects are **adults**, this exemption applies
    **UNLESS**: (a) information is recorded in an identifiable manner
    (either directly or indirectly using codes or other identifying
    links); **AND** (b) disclosure of the information would place the
    subject at risk of criminal or civil liability or be damaging to the
    subject's financial standing, employability, or reputation.
    *([Note]{.underline}**:** The research is exempt unless both (a)
    and (b) apply; i.e., the research is exempt unless the information
    collected is both identifiable and sensitive, except in the case of
    children as follows.)*

(2) This exemption applies to research involving **children,** EXCEPT
    that: (a) research involving survey or interview procedures with
    children is NOT EXEMPT; and (b) research involving observation of
    the public behavior of children is NOT EXEMPT if the investigator
    participates in the actions being observed.

(3) If not exempt under the conditions described above, research
    involving the use of educational tests (cognitive, diagnostic,
    aptitude, achievement), survey procedures, interview procedures, or
    the observation of public behavior is exempt where: (a) the subjects
    are elected or appointed public officials or candidates for public
    office; or (b) federal statutes require confidentiality without
    exception. *([Note]{.underline}: Condition (b) regarding federal
    statutes rarely applies. The IRB should consult with ORCA and OHRP
    if it receives an exemption request based on absolute
    confidentiality under a federal statue.)*

(4) If not exempt under the conditions described above, the IRB may
    often utilize expedited procedures for review and approval of
    research involving the use of educational tests (cognitive,
    diagnostic, aptitude, achievement), survey procedures, interview
    procedures, or the observation of public behavior. See item "h"
    below.

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g.  **Exempt Research Using Existing Data and Documents.** Social and
    behavioral research often relies on analysis of existing data or
    documents. Such research, which is often exempt, was discussed in
    Chapter 8 and will be discussed further in Chapter 14.

h.  **Expedited Review of Behavioral and Social Science Research** that
    presents no greater than minimal risk to subjects and fits one (or
    more) of the nine categories specified in the November 9, 1998,
    Federal Register FR 60364-60367 and FR 60353-60356 (see
    Appendix VII) may be reviewed by the IRB utilizing expedited
    procedures (see Chapter 9).

> The categories discussed below are particularly applicable to social
> and behavioral research, and include research involving children as
> well as adult subjects.

i.  **Expedited Review of Research Involving Existing Data and Documents
    (Expedited Category #5)*.*** Minimal risk research involving
    materials, (including data, documents, records, or specimens) that
    have been collected, or will be collected solely for non-research
    purposes, may be reviewed using expedited procedures.
    *([Note]{.underline}: The intent is to define two categories here,
    each appropriate for expedited review.)*

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(1) Non-exempt research involving materials that have already been
    collected (for any previous research or non-research purpose) at the
    time when the research is proposed.

(2) Non-exempt research involving materials that will be collected in
    the future for a non-research purpose.

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j.  **Expedited Review of Research Involving Data from Voice, Video,
    Digital, or Image Recordings Made for Research Purposes (Expedited
    Category #6).** The IRB may utilize expedited procedures to review
    research that involves the collection of data from voice, video,
    digital, or image recordings made for research purposes.

k.  **Expedited Review of Research Involving Individual or Group
    Characteristics or Behavior or Research Employing Survey, Interview,
    Oral History, Focus Group, Program Evaluation, Human Factors
    Evaluation, or Quality Assurance Methodologies (Expedited Category
    #7).** The IRB may utilize expedited procedures to review the
    following:

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(1) Research on individual or group characteristics or behavior, or

(2) Research employing survey, interview, oral history, focus group,
    program evaluation, human factors evaluation, or quality assurance
    methodologies.

(3) This category covers a wide range of non-exempt social and
    behavioral research activities when they present no greater than
    minimal risk to subjects. Examples include, but are not limited to,
    research on perception, cognition, motivation, identification,
    language, communication, cultural beliefs or practices.

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l.  **Research Involving Deception or Withholding of Information.** IRBs
    reviewing research involving incomplete disclosure or outright
    deception must apply both common sense and sensitivity to the
    review.

> Where deception is involved, the IRB needs to be satisfied that the
> deception is necessary and that, when appropriate, the subjects shall
> be debriefed. (Debriefing may be inappropriate, for example, when the
> debriefing itself would present an unreasonable risk of harm without a
> corresponding benefit.) The IRB should also make sure that the
> proposed subject population is suitable.
>
> Deception can only be permitted where the IRB documents that a waiver
> of the usual informed consent requirements is justified under the
> criteria present in VA regulations and the Common Rule and 38 CFR
> 16.116(d). Specifically, the IRB must find and document that all four
> of the following criteria have been satisfied (see Chapter 11):

(1) The research presents no more than minimal risk to subjects.

(2) The waiver or alteration shall not adversely affect the rights and
    welfare of the subjects.

(3) The research could not practicably be carried out without the waiver
    or alteration.

(4) Where appropriate, the subjects shall be provided with additional
    pertinent information after participation.

> In making the determination to approve the use of deception under a
> waiver of informed consent, the IRB should consider each criterion in
> turn, and document specifically (in the minutes of its meeting and/or
> in the IRB protocol file) how the proposed research satisfies that
> criterion. *([Note]{.underline}: The regulations make no provision for
> the use of deception in research that poses greater than minimal risks
> to subjects.)*

**[Chapter 13]{.underline}: Institutional Review Board (IRB) Review of
Research Using Data and Specimens**

Many studies combine characteristics of behavior and social research
with characteristics of biomedical research. There are many
interdisciplinary combinations of behavioral and medical research. They
often use or create tissue, specimen, or data repositories (banks).

a.  **Prospective Use of Existing Materials.** Prospective studies are
    designed to observe outcomes or events (e.g., diseases, behavioral
    outcomes, or physiological responses) that occur subsequent to
    identifying the targeted group of subjects, proposing the study, and
    initiating the research.

    1.  Prospective studies using materials (data, documents, records or
        specimens) that will "exist" in the future because they will be
        collected for some purpose unrelated to the research (e.g.,
        routine clinical care) do **not** qualify for **exemption**
        under VA regulations at 38 CFR 16.101(b)(4) and the Common Rule
        because the materials in these studies are not in existence at
        the time the study is proposed and initiated.

    2.  However, IRBs may utilize **expedited procedures** (under
        expedited category #5, see Chapters 10 and 14) to review
        research that proposes to use materials (i.e., data, documents,
        records, or specimens) that will be collected in the future
        (i.e., after the research has been proposed and initiated) for
        non-research purposes (e.g., clinical observations, medical
        treatment, or diagnosis occurring in a non-research context).

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b.  **Retrospective Use of Existing Materials.** Retrospective studies
    involve research conducted by reviewing materials (data, documents,
    records, or specimens) collected in the past (e.g*.,* medical
    records, school records, or employment records) and existing at the
    time the research is proposed and initiated.

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(1) Such research may be exempt under Department of Veterans Affairs
    (VA) regulations at 38 CFR 16.101(b)(4) if the information is
    publicly available or if the information is recorded in such a
    manner that subjects cannot be identified, either directly or
    through identifiers linked to the subjects (Chapter 9).

(2) If not exempt, the IRB may review such research utilizing expedited
    procedures, provided that the research involves no more than minimal
    risk to subjects (see Chapter 10).

(3) However, retrospective studies using existing materials occasionally
    entail significant, greater than minimal risks and require review by
    the convened IRB (e.g., where the research reveals previously
    undisclosed illegal drug use and the expedited review had concerns
    about invasion of subjects' privacy and/or the adequacy of
    confidentiality protections proposed by the investigators).

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c.  **Research Utilizing Large Existing Data Sets.** Biosocial and
    bio-behavioral research often involves the use of large, existing
    data sets.

> When the data sets are publicly available (i.e., available to the
> general public, with or without charge), their use is exempt, even if
> they contain sensitive, identifiable information (see Chapter 9 and
> item "2" above). Of course, use of data from publicly available data
> sets would still be exempt if the information is not sensitive or not
> identifiable.
>
> The use of large, existing data sets requires IRB review when they
> contain identifiable private information about living individuals. In
> such cases, the IRB must determine whether the information can be used
> without additional informed consent from the subjects.

(1) In making this determination, the IRB should first examine the
    conditions of informed consent under which the data were originally
    obtained. It may be that the proposed research is permissible under
    the original terms of consent.

(2) If this is not the case, then the IRB should consider whether it is
    permissible to waive the usual informed consent requirements in
    accordance with 38 CFR 16.116(d). Many times, a waiver of consent
    will be appropriate.

(3) In other cases, the IRB may determine that the research can proceed
    only if the investigator obtains and uses "anonymized" data. Under
    this scenario, codes and other identifiers are permanently removed
    from the data set before the data are sent to the investigator, and
    the removal is accomplished in such a manner that neither the
    investigator nor the source maintaining the data set can
    re-establish subjects' identities.

(4) An alternative to anonymizing data is to maintain the data set as a
    data repository under the guidelines established by the Office for
    Human Research Protections (OHRP) and VA (see Appendices VII).

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d.  **Research Using Data or Tissue Banks (also called Repositories).**
    Human data repositories collect, store, and distribute identifiable
    information about individual persons for research purposes. Human
    tissue repositories collect, store, and distribute identifiable
    human tissue materials for research purposes.

> VA policy (see Appendix VI, "Banking of Human Research Subjects'
> Specimens" VA Directive 2000-043, ORD Memo of March 28, 2001, and ORCA
> Guidance #19) specifies that human biological specimens, as well as
> the linked clinical data collected as part of research projects
> conducted by VA investigators in VA facilities or approved off-site
> locations, must be maintained at VA-approved tissue banks, whether the
> research is funded or unfunded, and regardless of the funding source.
>
> Tissue Bank activities involve three components: (a) the
> **collectors** of data or tissue samples; (b) the **bank/repository**
> storage and data management center; and (c) the **recipient**
> investigators. Under a repository arrangement, an IRB formally
> oversees all elements of repository activity, setting the conditions
> for collection, secure storage, maintenance, and appropriate sharing
> of the data and/or tissues with external investigators. Specifically,
> the IRB determines the parameters for sharing data and/or tissues
> (which are identifiable within the repository) in a manner such that
> additional informed consent of subjects is, or is not, required. (See
> OHRP guidance in Appendix VII.)
>
> Typically, these parameters involve formal, written agreements
> stipulating conditions as follows:

(1) The repository shall not release any identifiers to the
    investigator.

(2) The investigator shall not attempt to recreate identifiers, identify
    subjects, or contact subjects.

(3) The investigator shall use the data only for the purposes and
    research specified.

(4) The investigator shall comply with any conditions determined by the
    repository IRB to be appropriate for the protection of subjects.
    Additional information about the operation of data repositories can
    be found in Appendix VI.

**[Chapter 14]{.underline}: Institutional Review Board (IRB)
Considerations about Ethical Study Design**

a.  **Epidemiological Research.** Epidemiological research often makes
    use of sensitive, individually identifiable, private information
    (usually obtained from medical or other private records), and links
    this information with additional information obtained from other
    public or private records, such as employment, insurance, or police
    records. Epidemiological research may also combine historical
    research with survey and interview research.

> Epidemiological studies often present significant problems regarding
> both **privacy** and **confidentiality**.

(1) The IRB must first consider privacy issues, and must satisfy itself
    that the research does not constitute an unwarranted invasion of the
    subjects' privacy. In doing so, the IRB shall seek to establish that
    the investigator has legitimate access to any identifiable
    information that is to be utilized. For example, if State disease
    registry information is to be utilized, the IRB will need to examine
    State law relative to the legitimate release of such information for
    research.

(2) Once the IRB's privacy concerns have been resolved, the IRB will
    examine mechanisms for maintaining the confidentiality of data
    collected. The IRB shall seek to establish that confidentiality
    protections are appropriate to the nature and sensitivity of the
    information that has been obtained.

(3) Because epidemiological research typically requires large numbers of
    subjects, investigators almost always request that the IRB waive the
    usual requirements for informed consent. To approve such a waiver in
    epidemiological research, the IRB must find and document that the
    criteria for a waiver of informed consent have been met (38 CFR
    16.116(d); specifically that (a) the research presents no more than
    minimal risk to subjects; (b) the waiver will not adversely affect
    the rights and welfare of the subjects; (c) the research could not
    practicably be carried out without the waiver, and (d) whenever
    appropriate, the subjects will be provided with additional pertinent
    information after participation.

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b.  **Issues in Genetic Research.** Information obtained through genetic
    research may have serious repercussions for the subject or the
    subject's family members. Genetic studies that generate information
    about subjects\' personal health risks can provoke anxiety and
    confusion, damage familial relationships, and compromise the
    subjects\' insurability and employment opportunities. For many
    genetic research protocols, these psychosocial risks can be
    significant enough to warrant careful IRB review and discussion.
    Those genetic studies limited to the collection of family history
    information and blood drawing should not automatically be classified
    as \"minimal risk\" studies qualifying for expedited IRB review. The
    addition of the genetic analysis can radically alter the level of
    risk.

> The protection of private information gathered for and resulting from
> genetic research is a major concern. The IRB should expect the
> investigator to describe in detail how individual privacy will be
> protected and how the confidentiality of obtained information will be
> maintained. (See Chapter 3. Types of Research.)

c.  **Family History Research.** Family history research is a common
    technique used in bio-social and bio-behavioral research. Family
    history research typically involves obtaining information from one
    family member (called a proband) about other family members (third
    parties).

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(1) It is important to recognize the VA regulations at 38 CFR 16.102
    (f)(2) and the Common Rule include in the definition of human
    subject a living individual about whom an investigator obtains
    "identifiable private information."

(2) Thus, the family members identified and described by the proband may
    be human subjects under the regulations if the investigators obtain
    identifiable private information about them.

(3) IRBs must determine whether family members (third parties) are human
    subjects in such research, and if so, consider the possible risks
    involved, and determine whether their informed consent is required
    or can be waived (see Chapter 10) under the conditions specified at
    38 CFR 16.116(d). There is not total consensus in the available
    guidance on this issue. OHRP representatives have advised that
    "third parties" about whom identifiable and private information is
    collected in the course of research are human subjects.
    Confidentiality is a major concern in determining if minimal risk is
    involved. IRB\'s can consider if informed consent from third parties
    can be waived in accordance with Section.116 and if so, document
    that in the IRB minutes. In most cases waiver of consent may be
    appropriate.

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d.  **Research Involving Potentially Addictive Substances.** Research
    involving potentially addictive substances often involves the use of
    what may be termed "abuse-liable" substances. Abuse-liable
    substances are pharmacological substances that have the potential
    for creating abusive dependency. Abuse-liable substances can include
    both legal and illicit drugs. The following are among the issues
    that the IRB should consider when reviewing research involving
    potentially addictive substances:

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(1) When this type of research is proposed, the IRB must consider the
    subjects' capacity to provide continuous informed consent, ensuring
    that subjects are competent and are not coerced.

(2) If such research involves subjects that are institutionalized, the
    subjects' ability to exercise autonomy could be impaired.

(3) The IRB must also consider the requirements for equitable selection
    of subjects and protections for maintaining confidentiality, as such
    a population may be at risk for being discriminated against, or
    over-selected.

(4) The IRB must be sensitive to the ethical context of the research, in
    that there may be moral dilemmas associated with the use of
    placebos, or in cases where addicts are presented with alcohol
    and/or drugs.

(5) It is critical that the IRB focus on the considerations of risk and
    benefit of such research.

**[Chapter 15]{.underline}: Potentially Vulnerable Subject Groups**

Department of Veterans Affairs (VA) regulations at 38 CFR 16.111(b),
Food and Drug Administration (FDA) regulations, and the Common Rule
require IRBs to give special consideration to protecting the welfare of
particularly vulnerable subjects, such as children, prisoners, pregnant
women, mentally disabled persons, or economically or educationally
disadvantaged persons. Because veterans have a history of obeying orders
and making sacrifices, and because some veterans may not have access to
other health care, some might consider veterans a potentially vulnerable
population.

The IRB is also required to ensure that it has adequate representation
on the Board to consider specific kinds of research involving these
vulnerable populations in a satisfactory manner.

a.  **Elements to Consider in Reviewing Research Involving Vulnerable
    Subjects.** IRBs must pay special attention to specific elements of
    the research plan when reviewing research involving vulnerable
    subjects.

    1.  Strategic issues include inclusion and exclusion criteria for
        selecting and recruiting participants; informed consent and
        willingness to volunteer; coercion and undue influence; and
        confidentiality of data.

    2.  The IRB should carefully consider group characteristics, such as
        economic, social, physical, and environmental conditions, to
        ensure that the research incorporates additional safeguards for
        vulnerable subjects.

    3.  Investigators should not be permitted to over-select or exclude
        certain groups based on perceived limitations or complexities
        associated with those groups. For example, it is not appropriate
        to target prisoners as research subjects merely because they are
        a readily available "captive" population.

    4.  IRBs must be knowledgeable about applicable state or local laws
        that bear on the decision-making abilities of potentially
        vulnerable populations. State statutes often address issues
        related to competency to consent for research, emancipated
        minors, legally authorized representatives, the age of majority
        for research consent, and the waiver of parental permission for
        research. Copies of these statutes are attached in Appendix VII.

    5.  Just as in providing medical care, research studies that plan to
        involve any potentially vulnerable populations must have
        adequate procedures in place for assessing and ensuring
        subjects' capacity, understanding, and informed consent or
        assent. When weighing the decision whether to approve or
        disapprove research involving vulnerable subjects, the IRB shall
        look to see that such procedures are a part of the research
        plan. In certain instances, it may be possible for researchers
        to enhance understanding for potentially vulnerable subjects.
        Examples include requiring someone not involved in the research
        to obtain the consent, the inclusion of a consent monitor, a
        subject advocate, interpreter for hearing-impaired subjects,
        translation of informed consent forms into languages the
        subjects understand, and reading the consent form to subjects
        slowly and ensuring their understanding paragraph by paragraph.

    6.  The IRB may require additional safeguards to protect potentially
        vulnerable populations. For instance, the IRB may require that
        the investigator submit each signed informed consent form to the
        IRB, that someone from the IRB oversee the consent process, or
        that a waiting period be established between initial contact and
        enrollment to allow time for family discussion and questions.

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b.  **Pregnant Women, Fetuses, and Human In Vitro Fertilization**. The
    Department of Health and Human Services (DHHS) regulations at 45 CFR
    Part 46, Subpart B detail special protections for research involving
    pregnant women, fetuses, or human in vitro fertilization. Under
    these regulations, the IRB is required to document specific findings
    to minimize the potential for risk or harm to the fetus, and
    additional attention must be given to the conditions for obtaining
    informed consent.

> On the other hand, unilateral exclusion of non-pregnant women of
> reproductive potential from research should not be permitted by the
> IRB. Exclusion requires compelling scientific justification. Where
> such justification exists, it may also be appropriate to exclude men
> of reproductive potential.
>
> In general, Subpart B requires that research involving pregnant women
> and fetuses should involve the least possible risk. Persons engaged in
> the research may have no part in matters relating to the termination
> of the pregnancy, or to determine the viability of the fetus. No
> inducements may be offered to terminate a pregnancy.
>
> Four separate conditions, each with their own requirements and IRB
> determinations, apply to research with pregnant women and fetuses, as
> outlined below.

(1) **Research Involving Pregnant Women.** No pregnant women may be
    involved as a subject in research unless either of the following
    conditions apply: The purpose of the activity is to meet the health
    needs of the mother, and the fetus shall be placed at risk only to
    the minimum extent necessary to meet such needs; **OR** the risk to
    the fetus is minimal. The mother and the father must be legally
    competent and provide consent, unless the purpose of the research is
    to meet the health needs of the mother, or the father is not
    reasonably available, or the pregnancy resulted from rape.

(2) **Research Directed Toward the Fetus *In Utero*.** The IRB must find
    that: the purpose of the research is to meet the health needs of the
    individual fetus and shall be conducted in a way that will minimize
    risk; **OR** the research will pose no more than minimal risk to the
    fetus, and the purpose of the activity must be to ascertain
    important biomedical knowledge that is unobtainable by other means.
    These activities are permitted only if the mother and father are
    legally competent and have given their informed consent, unless the
    father is not reasonably available or the pregnancy resulted from
    rape.

(3) **Research Involving the Fetus *Ex Utero*.** For research involving
    fetuses *ex utero*, the IRB must distinguish between viable and
    non-viable fetuses. Viable is defined in the regulations as being
    able to survive to the point of independently maintaining heartbeat
    and respiration, given the benefit of available medical therapy. If
    the fetus is viable, it is a child and may be involved in research
    to the extent permissible under 45 CFR Part 46, Subpart D, which is
    discussed later in this chapter.

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(a) A **non-viable fetus** may not be involved in research unless all of
    the following conditions apply: The vital functions of the fetus
    shall not be artificially maintained; experimental activities that
    would of themselves terminate the heartbeat or respiration shall not
    be employed; **AND** the purpose of the research is development of
    important biomedical knowledge that cannot be obtained by other
    means.

(b) A **fetus of undetermined viability** may not be involved in
    research unless one of the following conditions applies: There will
    be no added risk to the fetus and the purpose of the research is to
    obtain important biological knowledge that cannot be obtained by
    other means; **OR** the purpose of the activity is to enhance the
    probability of survival of the individual fetus. Research involving
    a non-viable fetus or a fetus of undetermined viability is permitted
    only if the mother and father are legally competent and have given
    their informed consent, unless the father is not reasonably
    available or the pregnancy resulted from rape.

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(4) **Research Involving Dead Fetuses, Fetal Material, or the Placenta**
    must be conducted in accordance with any applicable State or local
    laws regarding such activities.

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c.  **Research Involving Prisoners.** DHHS regulations at 45 CFR 46,
    Subpart C detail special protections for research involving
    prisoners, who due to their incarceration may have a limited ability
    to make truly voluntary and uncoerced decisions about whether or not
    to participate as subjects in research. OHRP discourages expedited
    review of any research involving prisoners as participants.

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(1) A prisoner is defined as any individual involuntarily confined or
    detained in a penal institution.

(2) In order to consider research involving prisoners, IRBs must:

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(a) Have a majority of its members not otherwise associated with the
    prison.

(b) Include a prisoner or a prisoner advocate, who can adequately
    represent the interests of the prisoners, unless the research has
    already been reviewed by an IRB that included a prisoner advocate.

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(3) IRBs that approve research involving prisoners must:

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(a) Make the seven additional findings set forth in 45 CFR 46.305

(b) Determine which category in 45 CFR 46.306 permits the research to go
    forward

(c) If the research is DHHS-supported, certify these findings to the
    Office for Human Research Protections (OHRP). Certification to OHRP
    is not required for research not supported by DHHS. However, OHRP
    recommends that the IRB apply the standards of Subpart C to all
    prisoner research. Should non-DHHS research fall outside the
    category stipulations under 45 CFR 46.306, OHRP recommends that the
    IRB consult with appropriate experts before approving the research.
    (See "5" below)

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(4) Under DHHS regulations, prisoners may participate in the following
    categories of research:

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(a) Studies (involving no more than minimal risk or inconvenience) of
    the possible causes, effects, and processes of incarceration and
    criminal behavior.

(b) Studies (involving no more than minimal risk or inconvenience) of
    prisons as institutional structures or of prisoners as incarcerated
    persons.

(c) Research on particular conditions affecting prisoners as a class
    (providing the Secretary of HHS has consulted with appropriate
    experts and published the intent to support such research in the
    Federal Register).

(d) Research involving practices that have the intent and reasonable
    probability of benefiting the prisoner subject. If the research
    involves possible assignment to a control group that may not benefit
    from the research, the Secretary of HHS must also consult with
    appropriate experts and publish the intent to support the research
    in the Federal Register (45 CFR 46.306).

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(5) The following additional determinations must be made by the IRB
    before research involving prisoners goes forward (45 CFR 46.305):

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(a) The research under review represents one of the categories of
    research listed above.

(b) Any possible advantages accruing to the prisoner through his or her
    participation in the research, when compared with the general living
    conditions, medical care, quality of food, amenities and opportunity
    for earnings in the prison, are not of such a magnitude that his or
    her ability to weigh the risks of the research against the value of
    such advantages in the limited choice environment of the prison is
    impaired.

(c) The risks involved in the research are commensurate with risks that
    would be accepted by non-prisoner volunteers.

(d) Procedures for selecting subjects within the prison are fair to all
    prisoners, and immune from arbitrary intervention by prison
    authorities or prisoners. Unless the principal investigator provides
    to the IRB justification in writing for following some other
    procedures, control subjects must be selected randomly from the
    group of available prisoners who meet the characteristics needed for
    that particular research project.

(e) The information is presented in language that is understandable to
    the subject population.

(f) Adequate assurance exists that parole boards will not take into
    account a prisoner's participation in the research in making
    decisions regarding parole, and each prisoner is clearly informed in
    advance that participation in the research will have no effect on
    his or her parole.

(g) Where the IRB finds there may be a need for follow-up examination or
    care of participants after the end of their participation, adequate
    provision has been made for such examination or care, taking into
    account the varying lengths of individual prisoner's sentences, and
    for informing participants of this fact.

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d.  **Research Involving Children.** The VA is authorized to care for
    veterans and to conduct research that enhances the quality of health
    care delivery to veterans and is not authorized to care for the
    offspring of veterans. VA policy stipulates that children cannot be
    included in VA-approved research unless a waiver has been granted by
    the Chief Research and Development Officer (VA Directive 2001-028,
    dated April 27, 2001).

> DHHS regulations at 45 CFR 46, Subpart D require special protections
> for research involving children. Under the regulations, children are
> persons who have not attained the legal age for consent to treatments
> or procedures involved in the research under the applicable
> jurisdiction in which the research will be conducted. Applicable state
> laws are provided in Appendix VIII.
>
> There are three main issues to consider when reviewing research
> involving children: (1) risk-benefit analysis; (2) parental
> permission; and (3) assent of the child.

(1) IRBs must make certain findings and determinations when reviewing
    research involving children. IRB records must reflect the IRB's
    understanding and justification for the risks and benefits posed by
    approved research involving children. Proposed research must fall
    within one of the following four categories:

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(a) Research not involving greater than minimal risk.

(b) Research involving greater than minimal risk, but presenting the
    prospect of direct benefit to the individual subjects.

(c) Research involving greater than minimal risk and no prospect of
    direct benefit to individual subjects, but likely to yield
    generalizable knowledge about the subject's disorder or condition.

(d) Research not otherwise approvable, which presents an opportunity to
    understand, prevent, or alleviate a serious problem affecting the
    health or welfare of children.

> Each category stipulates specific conditions that must be met before
> the proposed research can be approved. These conditions are summarized
> in the Table at the end of this chapter.

(2) Provisions must also be made to obtain the child's assent when the
    IRB has determined that the child is capable of giving assent. The
    IRB should consider the age, maturity, and psychological state of
    the child involved. The IRB may determine that the assent of the
    child is not necessary if and only if all three of the following
    conditions are satisfied:

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(a) The research offers the child the possibility of a direct benefit.

(b) The benefit is important to the health or well being of the child.

(c) The benefit is available only in the context of the research.

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(3) IRBs should take great care in approving research where the child is
    suffering from a life-threatening illness with little real chance of
    therapeutic benefit from the research. IRBs should also be cautious
    in allowing the parents to overrule the child's dissent where
    experimental therapy has little or no reasonable expectation of
    benefit. The justification for exposing the child to extreme
    discomfort, with little possibility for benefit, may be tenuous at
    best.

(4) If it is deemed appropriate that the child's assent should be
    solicited, the IRB should ensure that the assent form is tailored
    for the child, with respect to his or her level of understanding.
    For young children, especially, the assent form should be designed
    as a one-page document, with simple, age-appropriate language, and
    presented in a manner understandable to the child. See table at end
    of this chapter.

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e.  **Research Involving Decisionally Impaired Subjects.** Decisionally
    impaired persons are individuals who have a diminished capacity for
    judgment and reasoning due to a psychiatric, organic, developmental,
    or other disorder that affects cognitive or emotional functions.
    Other individuals who may be considered decisionally impaired, with
    limited decision-making ability, are individuals under the influence
    of or dependent on drugs or alcohol, those suffering from
    degenerative diseases affecting the brain, terminally ill patients,
    and persons with severely disabling physical handicaps.

> There are no regulations specific to research involving cognitively
> impaired persons. However, there are specific VA policies that require
> certain findings to be made before persons incompetent to consent may
> be enrolled in research with the permission of a surrogate (see
> section 6a below).
>
> In all cases, IRBs should take special care to consider issues such as
> the selection of subjects, privacy and confidentiality, coercion and
> undue influence, and risk-benefit analysis. Decisions should be made
> with the utmost deference to the ethical principles underlying human
> subjects research as set forth in the Belmont Report. Capacity should
> be evaluated on an individual basis to avoid incorrect assumptions as
> to an individual's ability to make decisions. In cases where research
> involving cognitively impaired individuals is approved, IRBs should
> require additional safeguards (e.g., involvement of subject advocates,
> independent monitoring, formal capacity assessment, waiting periods)
> as part of the research plan to protect participants.
>
> The National Bioethics Advisory Commission (NBAC) has issued 21
> recommendations for IRBs, the research community, and Federal
> regulators to consider regarding the decision-making capacity of
> particularly vulnerable subjects. The complete report, "Research
> Involving Persons with Mental Disorders That May Affect Decision
> Making Capacity" (December 1998), can be found on-line at
> <http://bioethics.gov/capacity/TOC.htm>.

f.  **Surrogate Permission with Subjects Judged Incompetent to
    Consent**. VA policy (Cooperative Studies Program Guidance) limits
    the conditions under which consent from legally authorized
    representatives (i.e., surrogate consent) can be obtained in lieu of
    consent from the subject. Where consistent with state law, VA policy
    (M-3, Part 1, Chapter 9.12) recognizes as legally authorized
    representatives:

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(1) Persons appointed as health care agents under a Durable Powers of
    Attorney for Health Care (DPAHC).

(2) Court appointed guardians.

(3) Next of kin in the following order: spouse, adult child, parent, and
    adult sibling.

> Surrogate consent may be used only when the prospective subject is
> incompetent as determined by two VA physicians, after appropriate
> medical evaluation, and there is little or no likelihood that the
> subject will regain competence within a reasonable period of time, or
> as established by legal determination. This definition of incompetence
> is not limited to the legal definition but also may also be a clinical
> judgment that a person lacks the capacity to understand the
> circumstances of participating in research and to make an autonomous
> decision to take part.
>
> Before incompetent persons may be involved in any VA research, the IRB
> must find and document in writing that the proposed research meets all
> of the following conditions:

(1) Only incompetent persons are suitable. Competent persons are not
    suitable for the proposed research. The investigator must
    demonstrate that there is compelling reason to include incompetent
    persons as subjects. Incompetent persons must not be involved as
    subjects simply because they are readily available.

(2) Favorable Risk/Benefit Ratio. The proposed research entails no
    significant risks, or if the research presents risk of harm, there
    must at least be a greater probability of direct benefit to the
    subject than of harm.

(3) No Resistance. Subjects do not resist participating. Under no
    circumstances may subjects be forced or coerced into participating.

(4) Well-Informed Representatives. Procedures have been devised to
    ensure that subjects' representatives are well informed regarding
    their roles and obligations to protect the rights and welfare of the
    subjects they represent. Representatives must be informed in writing
    that their obligation is to try to determine what the subject would
    do if competent, or if the subject's wishes cannot be determined,
    what is in the subject's best interests.

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g.  **State Requirements.** IRB SOP should incorporate any State
    Requirements concerning vulnerable populations in an appendix.

h.  **Research Involving Other Potentially Vulnerable Adult Subjects.**
    Employees, students, and trainees in the VA Medical Center should
    also be considered vulnerable subjects. Thus, the IRB should uphold
    the same standards in approving research involving these groups as
    other vulnerable subjects research.

> The context of the research is an important consideration for IRBs to
> have in mind when reviewing research that involves other potentially
> vulnerable subjects. Research involving homeless persons, members of
> particular minority groups, or the economically or educationally
> disadvantaged pose significant challenges. Research involving
> significant follow-up procedures or offering significant monetary
> compensation may unduly influence certain types of subjects, and IRBs
> must take such considerations into account. Nevertheless, research
> involving these subjects is socially important for understanding and
> eventually improving adverse health in these populations.

i.  **Human Fetal Tissue Transplantation Research.** Public Law 103-43
    governs human fetal tissue transplantation research supported by
    DHHS as follows:

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(1) Human fetal tissue may be used only if the women providing the
    tissue declare in a signed written statement that she is donating
    the tissue without any restrictions regarding the identity of the
    transplant recipients and without being informed of the identity of
    the recipients.

(2) If the tissue is obtained pursuant to an induced abortion, the
    attending physician must declare in a signed written statement that
    the consent of the women for the abortion was obtained prior to
    requesting or obtaining consent for the donation of the tissue; no
    alteration of the timing, method, or procedures used to terminate
    the pregnancy was made solely for the purpose of obtaining the
    tissue; and the abortion was performed in accordance with applicable
    State law.

(3) The attending physician must declare in a signed written statement
    that the tissue was donated by the woman as described in item "a"
    and with full disclosure with regard to the physician's interest in
    the research and any known medical or privacy risks associated with
    the research.

(4) The principal investigator for the research must declare in a signed
    written statement that the tissue is human fetal tissue; the tissue
    may have been obtained pursuant to a spontaneous or induced abortion
    or stillbirth; the tissue was donated for research; the investigator
    has provided this information to other individuals involved in the
    research; the investigator shall require written acknowledgement of
    receipt of this information by the recipient; and the investigator
    has had no part in decisions as to the timing, method, or procedures
    used to terminate the pregnancy solely for the purposes of the
    research.

(5) It is unlawful for any person to knowingly acquire, receive, or
    transfer any human fetal tissue for valuable consideration.

(6) It is unlawful for any person to solicit or knowingly acquire,
    receive, or accept a donation of human fetal tissue for
    transplantation if the tissue is obtained pursuant to an induced
    abortion and the donation is made pursuant to a promise that it will
    be transplanted to any specified individual, to a relative of the
    donating individual, or in valuable consideration for the costs
    associated with the abortion.

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j.  **Research Involving Deceased Persons.** Research involving deceased
    persons is not covered by the VA or FDA human subject regulations or
    the Common Rule. However, such research may be covered under
    applicable state law.

**Research Involving Children**

+----------------------------------+-----------------------------------+
| **IRB Consideration**            | **Requirements**                  |
+----------------------------------+-----------------------------------+
| > **No Greater Than Minimal      | > Assent of child and permission  |
| > Risk**                         | > of at least one parent          |
+----------------------------------+-----------------------------------+
| > **Greater Than Minimal Risk    | > Assent of child and permission  |
| > and Prospect of Direct         | > of at least one parent          |
| > Benefit**                      |                                   |
+----------------------------------+-----------------------------------+
|                                  | > Anticipated benefit justifies   |
|                                  | > the risk                        |
+----------------------------------+-----------------------------------+
|                                  | > Anticipated benefit is at least |
|                                  | > as favorable as that of         |
|                                  | > alternative approaches          |
+----------------------------------+-----------------------------------+
| > **Greater Than Minimal Risk    | > Assent of child and permission  |
| > and**                          | > of both parents                 |
| >                                |                                   |
| > **No Prospect of Direct        |                                   |
| > Benefit**                      |                                   |
+----------------------------------+-----------------------------------+
|                                  | > Only a minor increase over      |
|                                  | > minimal risk                    |
+----------------------------------+-----------------------------------+
|                                  | > Likely to yield generalizable   |
|                                  | > knowledge about the child's     |
|                                  | > disorder or condition that is   |
|                                  | > of vital importance for the     |
|                                  | > understanding or amelioration   |
|                                  | > of the disorder or condition    |
+----------------------------------+-----------------------------------+
|                                  | > The intervention or procedure   |
|                                  | > presents experiences to the     |
|                                  | > child that are reasonably       |
|                                  | > commensurate with those in the  |
|                                  | > child's actual or expected      |
|                                  | > medical, dental, or expected    |
|                                  | > medical, dental, psychological, |
|                                  | > social, or educational          |
|                                  | > situations                      |
+----------------------------------+-----------------------------------+
| > **Any Other Research**         | > Assent of child and permission  |
|                                  | > of both parents                 |
+----------------------------------+-----------------------------------+
|                                  | > 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             |
+----------------------------------+-----------------------------------+
|                                  | > The HHS Secretary approves,     |
|                                  | > after consultation with a panel |
|                                  | > of experts in pertinent         |
|                                  | > disciplines (e.g., science,     |
|                                  | > medicine, education, ethics,    |
|                                  | > law) and following publication  |
|                                  | > in the Federal Register and     |
|                                  | > public comment                  |
+----------------------------------+-----------------------------------+

**[Chapter 16]{.underline}: Managing Conflicts of Interest**

Conflict of Interest can be defined as any situation in which financial
or personal obligations may compromise or present the appearance of
compromising an individual's or group's professional judgment in
conducting, reviewing, or reporting research.

Research personnel, IRB members, IRB Chairpersons, managers in the VA
Medical Center (VAMC) Research and Development Office, the Institutional
Official, and research sponsors may all have certain conflicts of
interest. Such conflicts of interest may arise because of the
intellectual property involved in many research discoveries or
industry-academic partnerships, from financial incentives many
pharmaceutical or biotech companies offer researchers or physicians for
conducting trials or enrolling subjects, or due to particular role
relationships within the governance structure of particular
institutions.

a.  **Research Personnel**. For researchers, financial or other
    incentives may negatively impact the collection, analysis and
    interpretation of data, scientific objectivity and integrity, and
    ultimately the public trust in the research enterprise. In addition,
    if also the treating physician, a researcher may unwittingly exert
    coercion or undue influence on patients to participate in research.

b.  **IRB Chairpersons and Members**. IRB chairpersons and IRB members
    may find themselves in any of the following conflicts of interest
    when reviewing research:

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(1) Where the IRB Chairperson or member is listed as an investigator on
    the research.

(2) Where any investigator must report to or is under the supervision of
    an IRB chairperson or member.

(3) Where the IRB Chairperson or member competes for research grants or
    contracts in the same or similar field as an investigator whose
    research is scheduled for review.

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c.  **IRB Administrator.** In VA not all IRB Administrators are full
    time. Many have other duties in the Research and Development Office.

d.  **Institutional Officials**. To avoid possible conflict of interest
    among institutional officials, the VA Medical Center Director, Chief
    of Staff, and Associate Chief of Staff for Research and Development
    (ACOS/R&D) should not serve unless there are compelling reasons
    [to]{.underline} serve, as voting members of the VAMC's designated
    IRB(s), current VA policy is silent on this issue, OHRP guidance is
    that those who administer the research programs have access to wider
    knowledge, have the ability to influence programmatic and budgetary
    decisions, and are in a position to exert undue influence on the
    IRB. Additionally, the ACOS/R&D is already a voting member of the
    R&D Committee that oversees the IRB.

e.  **VA Regulations and the Common Rule.** The VA human subject
    regulations at (38 CFR 16.107(e)), the Common Rule, and FDA prohibit
    IRB members, chairs, or staff who have a conflicting interest from
    participating in the IRB's initial or continuing review of research.

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(1) Such conflicts must be disclosed, and the IRB member, chairperson,
    or staff member must not take part in the discussion or voting of
    such research, except to answer questions from the IRB.

(2) IRBs may consider any matter that raises the possibility of coercion
    or undue influence in the consent process. The existence of an
    investigator conflict of interest would fall within this category.

(3) As a matter of policy, VAMCs should require disclosure of any
    potential conflicts of interest to appropriate facility officials or
    committees established for this purpose. Adherence to disclosure
    requirements is a routine condition for IRB approval of research and
    should appear in IRB standard operating procedure (SOP).

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f.  **FDA Requirements**. The FDA requires a sponsor in a marketing
    application of any drug, device, or biologic to submit certain
    information on financial interests and arrangements of clinical
    investigators conducting studies to FDA. The following financial
    arrangements must be disclosed:

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(1) Any relationship between the study outcome and the value of the
    compensation made to the investigator.

(2) The investigator's proprietary interest in the studied product,
    including but not limited to a patent, trademark, copyright or
    licensing agreement.

(3) Any equity interest in the study sponsor, ownership interest, stock
    options, or other financial interest.

(4) Any equity interest in a publicly held company that exceeds \$50,000
    in value.

(5) Significant payment of another type, which has a cumulative monetary
    value of \$25,000 or more, made by the sponsors to the
    investigator(s).

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g.  **The Department of Health and Human Services Public Health Service
    (DHHS-PHS) Requirements for Grantee Institutions**. DHHS requires
    that PHS grantee institutions have a written policy and guidelines
    on conflicts of interest.

> A designated institutional official is responsible for reviewing all
> financial disclosures, and determining if a conflict of interest
> exists. If one exists, the Institutional Official must determine what
> actions should be taken to manage, reduce, or eliminate the
> conflicting interest. IRB SOPs should include a reference identifying
> the person designated. "At this facility, the designated institutional
> conflict of interest official is
>
> ."
>
> The PHS requirements call for grantee institutions to:

(1) Maintain a written, enforced policy on conflicts of interest

(2) Review all financial disclosure statements (listings of significant
    financial interests for investigators and immediate family members)
    for all investigators participating in PHS-funded research

(3) Report to PHS the existence of a conflicting interest found by the
    institution and ensure that it has been managed

> Under this regulation, an "Investigator" means the principal
> investigator and any other person who is responsible for the design,
> conduct, or reporting of the research. For purposes of determining
> financial interests, the Investigator\'s interests include those of
> his/her spouse and dependent children. 
>
> "Significant financial interest" means anything of monetary value,
> including but not limited to, salary or other payments for services
> (e.g., consulting fees or honoraria); equity interests (e.g., stocks,
> stock options or other ownership interests); and intellectual property
> rights (e.g., patents, copyrights and royalties from such rights).
> Financial interests which are subject to reporting for any given
> research proposal include those which would reasonably appear to be
> affected by the specific research proposed; and/or are interests in
> entities whose financial interests would reasonably appear to be
> affected by the research.
>
> \"Significant financial interest\" does **not** include:

(1) Salary, royalties, or other remuneration from the applicant
    institution.

(2) Any ownership interests in the institution, if the institution is an
    applicant under the PHS Small Business Innovation Research Program.

(3) Income from seminars, lectures, or teaching engagements sponsored by
    public or nonprofit entities.

(4) Income from service on advisory committees or review panels for
    public or nonprofit entities.

(5) An equity interest that when aggregated for the Investigator and the
    Investigator\'s spouse and dependent children, meets both of the
    following tests: (a) Does not exceed \$10,000 in value as determined
    through reference to public prices or other reasonable measures of
    fair market value, and (b) does not represent more than a five
    percent ownership interest in any single entity.

(6) Salary, royalties or other payments that when aggregated for the
    Investigator and the Investigator\'s spouse and dependent children
    over the next twelve months, are not expected to exceed \$10,000.

> Examples of conditions or restrictions that might be imposed to manage
> conflicts of interest include, but are not limited to:

(1) Public disclosure of significant financial interests;

(2) Monitoring of research by independent reviewers;

(3) Modification of the research plan;

(4) Disqualification from participation in all or a portion of the
    research funded;

(5) Divestiture of significant financial interests; and

(6) Severance of relationships that create actual or potential
    conflicts.

> VAMCs should require that all investigators submit conflict of
> interest disclosure forms to the designated institutional conflict of
> interest official.

h.  **The Disclosure Process.** As one method of preventing, monitoring,
    managing, and resolving conflicts of interest, this facility
    requires full disclosure of conflicts of interest by investigators.

> Full disclosure of conflicting information demonstrates good faith and
> protects the integrity of the research and the reputation of the
> institution. Disclosure is made to this facility's institutional
> conflict of interest official, and where deemed appropriate by that
> official to the IRB.
>
> Where appropriate, and as determined by the IRB or the conflict of
> interest official, disclosure to the human subjects involved in the
> research may be warranted via the informed consent document.

E. Institutional Review Board (IRB) Management of Food and Drug
Administration (FDA) Regulated Research

**[Chapter 17]{.underline}: Investigational Drugs, Devices, and
Biologics**

The Food and Drug Administration (FDA) is a component of the U.S.
Department of Health and Human Services (DHHS). The FDA's mission is to
promote and protect the public health by helping safe and effective
products reach the market, and then monitoring these products for
continued safety after they are in use.

The FDA regulates clinical investigations (research) conducted on drugs,
biologics, devices, diagnostics, and, in some cases, dietary supplements
and food additives, hereinafter referred to as "FDA regulated test
articles." All such investigations must be conducted in accordance with
FDA requirements for informed consent and IRB review, regardless of
funding source or sponsor.

When an FDA regulated test article is used in research being done at the
VA or funded by another federal agency, more than one set of regulations
may apply. For example, clinical trials involving FDA regulated test
articles that are supported by DHHS (e.g., the National Institutes of
Health) fall under the jurisdiction of both the FDA and the DHHS Office
for Human Research Protections (OHRP). Such trials must comply with the
FDA and the DHHS human subject regulations as well as VA regulations and
the Common Rule. Where regulations differ, IRBs should apply the
stricter one.

a.  **FDA Requirements in Relation to VA, Common Rule, and DHHS
    Requirements.** The human subject protection requirements found in
    FDA regulations are substantially the same as the VA and Common Rule
    requirements. However, there are important differences:

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(1) The FDA has different definitions for "human subject" and "clinical
    investigation (research)."

(2) FDA regulations contain no Assurance requirement.

(3) Conditions for exemption, exception, and waiver of IRB review and
    informed consent requirements differ (see Chapters 8 and 10).

(4) FDA regulations require specific determinations for the IRB review
    of device studies (see below).

(5) FDA regulations include specific requirements for reporting adverse
    events that are not found in VA regulations, the Common Rule, or
    DHHS regulations.

(6) DHHS regulations include specific additional protections for
    pregnant women, fetuses, and human in vitro fertilization (Subpart
    B); prisoners (Subpart C); and children (Subpart D) that are not
    contained in the VA, and Common Rule requirements. In April 2001 FDA
    issued regulations to protect children in research (20 CFR 50
    Subpart D). In April 2001 the VA Office of Research and Development
    issued Directive 2001-028, requiring a centralized waiver.

In addition to regulations governing human subject protection, the FDA
also has regulations governing the use of investigational drugs and
biological drugs (21 CFR 312) and devices (21 CFR 812).

b.  **Additional VA Requirements.** VA policy (M-3, Part 1, Chapter 9)
    requires that all research comply with the VA human subject
    regulations, as well as with all applicable regulations and
    requirements regarding storage and security procedures for
    investigational agents.

    1.  A VA Investigational Drug Information Record (VA Form 10-9012)
        must be completed by the principal investigator, submitted to
        Pharmacy Service, and monitored by the Research and Development
        (R&D) Committee (M-3, Part 1, Chapter 9.15(3)).

    2.  Upon approval of the research by the IRB and R&D Committee, a
        Report of Subcommittee on Human Studies (VA Form 10-1223) must
        be forwarded to the investigator and the Chief of Pharmacy
        Service.

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c.  **Research Involving Investigational FDA Regulated Test Articles.**
    Medical products, such as drugs, biologics, and medical devices need
    to be proven safe and effective before the FDA can approve them for
    sale to and use by patients. FDA reviews the results of laboratory,
    animal and human clinical testing to determine if the product to be
    put on the market is safe and effective. New medical products that
    have not yet been approved for marketing by the FDA require a
    special status so they can be legally shipped for the purpose of
    conducting clinical investigations to establish safety and efficacy.

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(1) The IND is an investigational new drug application and is synonymous
    with "Notice of Claimed Investigational Exemption for a New Drug."
    Investigational new drug (or investigational drug) means a new drug
    or biological drug used in a clinical investigation. An
    investigational drug must have an IND before it can be shipped.

(2) An approved investigational device exemption (IDE) permits a device
    not approved by FDA to be shipped to conduct clinical investigations
    of that device. Not all investigational devices need an IDE. See
    section "6" below.

(3) With only a few exceptions, most clinical research being done on FDA
    regulated test articles with either an IND or IDE will need initial
    review at a convened IRB meeting.

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d.  **Investigator and Sponsor Responsibilities.** Under FDA
    regulations, the i**nvestigator** in a clinical trial is responsible
    for the conduct of the study and for leading the team of individuals
    coordinating the study. These responsibilities include:

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(1) Obtaining IRB approval;

(2) Getting informed consent from each subject;

(3) Following the investigational plan;

(4) Complying fully with the regulations;

(5) Protecting the rights, welfare and safety of the subjects;

(6) Supervising the use and disposition of the test article;

(7) Maintaining accurate, current and complete records; and

(8) Disclosing relevant financial information.

> The **sponsor** takes responsibility for initiating the clinical
> investigation, and holding the IND or IDE, but does not usually
> conduct the investigation. Although the sponsor is usually a
> pharmaceutical, biotech, or medical device company, an individual or
> group of individuals or medical center can also be considered a
> sponsor for an investigation. An investigator is referred to as the
> sponsor-investigator when the individual investigator is also the
> initiator of the clinical investigation. Some of the responsibilities
> of sponsors are:

(1) Selecting qualified investigators;

(2) Providing investigators with the information they need to conduct
    the investigation properly;

(3) Ensuring proper monitoring of the investigation; and

(4) Ensuring that the FDA and (for devices) any reviewing IRBs or (for
    drugs) all participating investigators are promptly informed of
    significant new information about an investigation.

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e.  **IRB Review of Medical Devices.** FDA device regulations
    differentiate between significant risk (SR) and non-significant risk
    (NSR) devices. A significant risk device must have an IDE, while a
    non-significant risk device does not. Thus, if a clinical
    investigation is submitted to an IRB for a device that has an IDE,
    the device is considered a SR device.

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(1) A SR device study presents a potential for serious risk to the
    health, safety, or welfare of a subject and (a) is intended as an
    implant, or (b) is used in supporting or sustaining human life,
    or (c) is of substantial importance in diagnosing, curing,
    mitigating or treating disease, or otherwise prevents impairment of
    human health.

(2) A NSR device study is one that does not meet the definition of a SR
    study.

> Under some circumstances, an IRB must determine whether a device
> involves significant risk (SR) or non-significant risk (NSR) to
> subjects. Because NSR studies do not require an IDE, a clinical
> investigation involving an investigational device classified by the
> sponsor as NSR may be submitted to an IRB for review without an IDE.
> The sponsor should provide the IRB with a risk assessment and the
> rationale used in making its NSR risk determination. In this
> situation, the IRB must review the information and make its own
> independent determination that the device is SR or NSR. IRBs that do
> research using investigational devices must have written procedures
> for making the NSR/SR determination.

(1) If the IRB determines that the study involves a SR device (disagrees
    with the assessment of the sponsor), then it would be governed by
    the IDE regulations at 21 CFR 812. The IRB would notify both the
    investigator and the sponsor of its determination, and the sponsor
    would need to submit an IDE application to the FDA. The study could
    not begin until the FDA approves the IDE and the IRB approves the
    study.

(2) If the IRB determines that the device is classified as NSR (concurs
    with the assessment of the sponsor), the clinical investigation may
    begin once IRB approval is obtained since the submission of an IDE
    application to the FDA is not required. *([Note]{.underline}: The
    terms "non-significant risk" and "minimal risk" are defined
    separately, and are not synonymous.)*

(3) If FDA agrees that a new device is substantially equivalent to a
    device already on the market, it can be marketed without clinical
    testing. However, if clinical data are necessary to demonstrate
    equivalence, any clinical studies must be conducted in compliance
    with the requirements of the IDE regulations, IRB review, and
    informed consent.

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f.  **Radiology Devices and Radioactive Materials.** FDA is responsible
    for regulating radiology devices and radioactive materials used in
    healthcare and research. Oversight at the VAMC is handled by the
    institutional Radiation Safety Committee (RSC), a subcommittee of
    the Research and Development Committee.

> Under 21 CFR 361.1, an institution may also have a Radioactive Drug
> Research Committee (RDRC) to review certain kinds of research using
> drugs "generally recognized as safe and effective." An RDRC is **not**
> the same as a Radiation Safety Committee and is **not** set up to
> provide investigators with a way of circumventing the IND regulations
> to avoid getting an IND for new radiopharmaceutical drugs.

(1) The RDRC, as defined in 21 CFR 361.1 has no oversight responsibility
    or authority over an investigation carried out under an IND
    exemption. This authority is retained by the FDA.

(2) The RDRC is distinct from all other investigational drug review
    committees within an institution, such as the RSC and the IRB. The
    approval of both of these committees, in addition to RDRC approval,
    is required before an RDRC investigation can be permitted to start.

(3) The RDRC is established and chartered by the FDA under 21 CFR 361.1.
    It is not regulated to any specific type of license granted by the
    Nuclear Regulatory Commission (NRC) or state regulatory bodies. The
    RDRC must be approved by the FDA, and its composition is established
    by regulation.

(4) The RDRC approves the research in accordance with standards set out
    in 21CFR361.1, and submits reports to the FDA at least once a year,
    using the format specified by the regulation.

> Since the RDRC may only review research using drugs that are
> "generally recognized as safe and effective," an RDRC must determine
> if the radiopharmaceutical in a particular research project both meets
> that definition and is being done only to obtain basic information.

(1) The research project only intended to obtain basic information
    regarding the metabolism (including kinetics, distribution, and
    localization) or human physiology, pathophysiology, or biochemistry
    of a radioactively labeled drug.

(2) The radioactive drugs being used are considered safe and effective
    only after the following determinations are made:

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(a) The amount of active ingredient or combination of active ingredients
    to be administered is [known]{.underline} not to cause any
    clinically detectable pharmacological effect in human beings.

(b) Under no circumstances does the radiation dose to an adult research
    subject (either from a single study or cumulatively from a number of
    studies conducted within 1 year) exceed limits specified by 21 CFR
    361.1.

(c) The amount of radioactive material to be administered is the
    smallest radiation dose the subject can practically receive to
    perform the study without jeopardizing the benefits to be obtained
    from the study.

(d) All radioactive material included in the drug, either as essential
    material or as a significant contaminant or impurity, was included
    when total radiation doses and dose commitments were determined.

(e) Radiation doses from x-ray procedures that are part of the research
    study (i.e., would not have occurred but for the study) and the
    possibility of follow-up studies were included in the dose
    calculations.

(f) Numerical definitions of dose were based on an absorbed fraction
    method of radiation absorbed dose calculation, such as the system
    set forth by the Medical Internal Radiation Dose Committee of the
    Society of Nuclear Medicine, or the system set forth by the
    International Commission on Radiological Protection.

(g) The radiation exposure is justified by the quality of the study and
    the importance of the information it seeks to obtain.

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(3) If all the above determinations cannot be made [and
    documented]{.underline}, the radiopharmaceutical may not be
    classified as "generally recognized as safe and effective," so the
    RDRC may not review and approve the research. An IND may be needed.

(4) Adverse events (AEs) are reported to both the IRB and RDRC.

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g.  **AEs and Reporting Requirements.** Some requirements for reporting
    AEs are the same, regardless of what sort of test article is used
    (e.g. a drug or a device). What is reported, when it should be
    reported, and to whom the report is made is summarized below and in
    sections **"i"** for drugs and biologics, and in **"j"** for
    devices. IRB SOPs should describe these reports, and specify time
    frames both for reporting to the IRB (if not already specified in
    the regulations) and for IRB review of the problem.

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(1) **General Investigator Reporting Responsibilities:** FDA, VA, and
    DHHS regulations require **prompt** reporting to the IRB, FDA, OHRP,
    and the Office of Research Compliance and Assurance (ORCA) of any
    unanticipated problems involving risks to human subjects and others.

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(a) FDA interprets "any unanticipated problems involving risks to human
    subjects" to mean "...an unexpected adverse experience that is not
    listed in the labeling for the test article. ...including an event
    listed in the labeling ...that differs ...because of greater
    specificity or severity" (FR 28027).

(b) FDA interprets "...and others" to mean "...persons who are
    participating in clinical trials under the same or similar protocols
    or who may be affected by products or procedures developed in those
    trials" (FR 28027).

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(2) **IRB Reports to the R&D Committee**: The IRB Chairperson provides
    **prompt** written notification of AEs to the R&D Committee.

> In its procedures, the VAMC should require that any AE information
> submitted to the sponsor by the investigator should also be submitted
> to the IRB. In addition to providing **prompt** written notification
> to relevant Federal agencies, including ORCA, FDA, and OHRP, of any
> unanticipated problems involving risks to subjects or others, the IRB
> should also report the resolution of those problems.

h.  **AEs and Reporting Requirements -- INDs.** FDA IND regulations (for
    both drugs and biologics) have requirements related to the reporting
    of adverse events.

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(1) **Investigator Reports to Sponsor:** FDA IND regulations require
    that the investigator report promptly to the sponsor any "adverse
    effect that may reasonably be regarded as caused by, or probably
    caused by, the drug. If the adverse effect is alarming, the
    investigator shall report the adverse effect immediately" (21 CFR
    312.64(b)).

(2) **Sponsor Reports to FDA and Investigators:** FDA IND regulations
    require that the sponsor notify the FDA and all participating
    investigators of any adverse experience associated with the use of
    the drug or biologic that is **both** serious **and** unexpected as
    soon as possible but **in no event later than 15 calendar days after
    the sponsor determines it to be reportable.**

The FDA should be notified by telephone, facsimile, or in writing as
soon as possible but **in no event later than 7 calendar days** **of the
sponsor's receipt of the information of any unexpected [fatal or
life-threatening]{.underline} experience.**

"Serious adverse drug experience" is defined as "any adverse drug
experience occurring at any dose that results in any of the following
outcomes: death, a life-threatening adverse drug experience, inpatient
hospitalization or prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or a congenital
anomaly/birth defect" (21 CFR 312.32(a)).

i.  **AEs and Reporting Requirements -- IDEs.** FDA IDE (device)
    reporting requirements for are similar but not exactly the same as
    for drugs and biologics.

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(1) **Investigator to Sponsor**: FDA IDE regulations require that the
    investigator notify the sponsor and the IRB of any unanticipated
    adverse device effect **within 10 days of discovery.**

(2) **Sponsor to FDA, Investigator, and IRB.** The sponsor is required
    to evaluate the event and report it to the FDA, to all participating
    investigators, and to all reviewing IRBs **within 10 working days**
    **of the sponsor's receipt of the information.**

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j.  **"Off-label" (Unapproved) Use of FDA-Regulated Products in Medical
    Practice.** The FDA approves the sale, use, and labeling of a
    product for specific indications (the reason the product is being
    used -- a disease, condition, as a diagnostic tool, etc.).
    "Off-label" or unapproved use is when the product is used in a way
    or on a population different from that for which it was approved.
    The IND regulations do not apply to the use of marketed drugs for
    unlabeled indications in the practice of medicine (21 CFR 312.2(d)).

k.  **"Off-label" (Unapproved) Use of FDA Regulated Products in
    Research.** Good medical practice and the best interests of the
    patient require that physicians use legally available, marketed
    drugs, biologics and devices according to their best knowledge and
    judgment. If physicians use a product for an indication not included
    in the approved labeling (i.e., off-label), they have the
    responsibility to be well informed about the product, to base its
    use on firm scientific rationale and on sound medical evidence, and
    to maintain records of the product's use and effects.

The FDA definition of research in the IND regulations is as follows:
"Clinical investigation" means any experiment in which a drug is
administered or dispensed to, or used involving, one or more human
subjects. For the purposes of this part, an experiment is any use of a
drug except for the use of a marketed drug in the course of medical
practice (21CFR312.3(a)) Thus, under the FDA IND regulations, it is
possible for one drug given to one person to be considered research.

> The off-label use of a marketed drug or biologic in **research** does
> require IRB review, informed consent and, under some circumstances,
> may require an IND. To be exempt from the requirements of the IND
> regulations, all the following must apply (note that includes the
> requirement of IRB review and informed consent):

(1) The investigation is not intended to support of a new indication for
    use nor any other significant change in the labeling for the drug;

(2) The investigation is not intended to support a significant change in
    the advertising for the product;

(3) The investigation does not involve a route of administration or
    dosage level or use in a patient population or other factor that
    significantly increases the risks (or decreases the acceptability of
    the risks) associated with the use of the drug product;

(4) The investigation is conducted in compliance with the requirements
    for institutional review board review and informed consent; and

(5) The investigation is conducted in compliance with the FDA
    regulations on promoting and charging for investigational drugs (21
    CFR 312.7).

> Use of an off-label marketed product in research intended to support
> **a new indication for use, change in labeling or advertising**
> requires IRB review, informed consent and submission of an IND.
>
> Using an off-label marketed product in research involving a route of
> administration or dosage level or use in a patient population or other
> factor that significantly increases the risks (or decreases the
> acceptability of the risks) associated with its use requires IRB
> review, informed consent and may also require submission of an IND.

### **Expanded Access to Investigational Drugs.** Investigational products are sometimes used for treatment of serious or life-threatening conditions either for a single subject or for a group of subjects. The procedures that have evolved for an investigational new drug (IND) used for these purposes reflect the recognition by the FDA that, when no satisfactory alternative treatment exists, subjects are generally willing to accept greater risks from test articles that may treat life-threatening and debilitating illnesses. The following mechanisms expand access to promising therapeutic agents without compromising the protection afforded to human subjects or the thoroughness and scientific integrity of product development and marketing approval (21 CFR 312.34, 312.35, and 312.83).

###  {#section .unnumbered}

(1) **Open Label Protocol or Open Protocol IND.** These are usually
    uncontrolled studies, carried out to obtain additional safety data
    (Phase III studies). They are typically used when the controlled
    trial has ended and treatment is continued so that the subjects and
    the controls may continue to receive the benefits of the
    investigational drug until marketing approval is obtained. These
    studies require prospective IRB review and informed consent.

(2) **Treatment IND.** The treatment IND (21 CFR 312.34 and 312.35) is a
    mechanism for providing eligible subjects with investigational drugs
    for the treatment of serious and life-threatening illnesses for
    which there are no satisfactory alternative treatments. A treatment
    IND may be granted after sufficient data have been collected to show
    that the drug \"may be effective\" and does not have unreasonable
    risks. Because data related to safety and side effects are
    collected, treatment INDs also serve to expand the body of knowledge
    about the drug. Four requirements must be satisfied before a
    treatment IND can be issued:

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(a) The drug must be intended to treat a serious or immediately life
    threatening disease;

(b) There must be no satisfactory alternative treatment available;

(c) The drug must already be under investigation or the drug trials must
    have been completed; and

(d) The trial sponsor must be actively pursuing marketing approval.

> Treatment IND studies require prospective IRB review and informed
> consent. VAMCs should stipulate in the IRB SOP and investigator
> education materials that all treatment IND studies must reviewed and
> prospectively approved by one of its designated IRBs.

(3) **Parallel Track Studies.** FDA also permits wider access to
    promising new drugs for HIV/AIDS related diseases under a "separate
    access" protocol that "parallels" the controlled clinical trials
    that are essential to establish the safety and effectiveness of new
    drugs. These so-called "parallel track" studies require prospective
    IRB review and informed consent.

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m.  **Expanded Access to Investigational Devices.** According to statute
    and FDA regulations, an unapproved medical device may normally only
    be used in human subjects when the device is under clinical
    investigation and when used by investigators participating in the
    clinical trial. FDA recognizes, however, that there may be
    circumstances under which a health care provider may wish to use an
    unapproved device to save the life of a patient, to prevent
    irreversible morbidity or to help a patient suffering from a serious
    disease or condition for which there exists no alternative therapy.
    Four main mechanisms are utilized by FDA to make unapproved devices
    available to patients/physicians faced with circumstances such as
    those described above. These mechanisms are consistent with the
    Expanded Access provisions of the FDA Modernization Act of 1997
    (Section 561 of the Federal Food, Drug, and Cosmetic Act). The
    sponsor must agree and FDA must approve the use. Under most
    circumstances such studies require IRB review and informed consent.

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(1) **Single Patient/Small Group Access to Investigational Devices.**
    Allows access to a device where patient is not eligible for an
    ongoing clinical trial. The subject must have a serious
    condition/disease, with no alternative intervention available. Under
    some conditions, FDA may grant permission even if there is no
    pre-existing IDE.

(2) **Treatment Use/IDE (21 CFR 812.36).** Allows wider access to a
    device during the clinical trial or prior to final action on
    marketing application. Again, the subject must have a serious
    condition/disease, with no alternative intervention available.

(3) **Continued Access to Investigational Devices.** Allows access to a
    device while a marketing application is being prepared and reviewed,
    and can be used to collect additional evidence of safety and
    effectiveness, as well as to address new questions regarding the
    investigational device, such as labeling claims. There must be a
    public health need for the device, as well as preliminary evidence
    that the device is effective.

(4) **Access under a formal protocol.** Access in a controlled rate of
    enrollment and with no significant safety concerns identified for
    the proposed indication.

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n.  **Gene Transfer Research.** Gene transfer involves the
    administration of genetic material to alter the biological
    properties of living cells for therapeutic use. Gene transfer
    activities in humans are investigational and are regulated by the
    both the FDA and the National Institutes of Health (NIH) Office of
    Biotechnology Activities (OBA).

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(1) FDA regulations require the submission of an IND for human gene
    transfer research through the FDA Center for Biologics.

(2) DHHS regulations specify that no individual may be enrolled in human
    gene transfer research until review has been completed by the NIH
    Recombinant DNA Advisory Committee (RAC), local Institutional
    Biosafety Committee (IBC) approval has been obtained, local IRB
    approval has been obtained, and the investigator has obtained all
    other regulatory authorizations from the subject (FR 196, October
    10, 2000).

(3) While the RAC is advisory to the Director of the NIH, compliance
    with its guidelines is mandatory for all investigators at
    institutions that receive NIH funds for research involving
    recombinant DNA.

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o.  **Emergency Use of a Test Article Without IRB Review.** An exemption
    under FDA regulations at 21 CFR 56.104(c) permits the emergency use
    of an investigational drug, device, or biologic on a one-time basis
    per institution without IRB review and approval. The first three of
    the following conditions must be met for this type of emergency use:

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(1) A human subject is in a life-threatening situation.

(2) No standard acceptable treatment is available.

(3) There is insufficient time to obtain IRB approval.

(4) The emergency use must be reported to the IRB within five working
    days. This reporting must not be construed as an approval for the
    emergency use by the IRB.

(5) Ordinarily, the investigator must obtain the informed consent of the
    subject for such an emergency use, except as described below.

> VA policy M-3, Part 1, Chapter 9.15(f)(2)(a) requires separate
> authorization from the Under Secretary for Health for patients outside
> a research protocol for each such emergency use of a test article
> without IRB review, as well as the filing of VA Form 10-9012
> Investigational Information Drug Record with the Chief of Pharmacy
> Services.

p.  **Emergency Use of a Test Article Without Informed Consent.** An
    exception under FDA regulations at 21 CFR 50.23 permits the
    emergency use of an investigational drug, device, or biologic
    without informed consent where the investigator and an independent
    physician who is not otherwise participating in the clinical
    investigation certify in writing all four of the following specific
    conditions:

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(1) The subject is confronted by a life-threatening situation
    necessitating the use of the test article;

(2) Informed consent cannot be obtained because of an inability to
    communicate with, or obtain legally effective consent from, the
    subject;

(3) Time is not sufficient to obtain consent from the subject's legally
    authorized representative;

(4) No alternative method of approved or generally recognized therapy is
    available that provides an equal or greater likelihood of saving the
    subject's life.

If time is not sufficient to obtain the independent physician
determination before use of the test article, the actions of the
investigator must be reviewed and evaluated in writing by an independent
physician within 5 working days. The emergency use must be reported to
the IRB within 5 working days. This reporting must not be construed as
an approval for the emergency use by the IRB. *([Note]{.underline}: This
use without prospective IRB approval is not research, but medical
treatment, and cannot be counted as research data.)*

q.  **"Compassionate" or "Humanitarian" Use of a Test Article.**
    Questions frequently arise regarding "compassionate" or
    "humanitarian" use of a test article. "Compassionate use" and
    "humanitarian use" are not terms that appear in the FDA, VA, or DHHS
    regulations or the Common Rule. "Compassionate use" and
    "humanitarian use" are often meant to refer to the emergency use
    situations discussed above.