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VII. RESEARCH INVOLVING SPECIAL CATEGORIES OF HUMAN SUBJECTS

7.1 Studies Involving Pregnant Women, Fetuses and Neonates as Subjects

The provisions in this section shall govern all research conducted by or at SHS involving pregnant women, fetuses and neonates as human subjects. The IRB shall determine that:

  • Adequate consideration has been given to the manner in which potential subjects will be selected; and
  • Adequate provision has been made for monitoring the actual informed consent process

7.1.1. Research Involving Pregnant Women and Fetuses

Before approving any research protocol directed toward pregnant women and fetuses, the IRB shall ensure all of the following conditions are met: (45 CFR 46.204):

  • Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on nonpregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses;
  • The risk to the fetus is caused solely by interventions or procedures that hold out the prospect of direct benefit for the woman or the fetus; or, if there is no such prospect of benefit, the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge which cannot be obtained by any other means;
  • Any risk is the least possible for achieving the objectives of the research;
  • If the research holds out the prospect of direct benefit solely to the fetus then the consent of the pregnant woman and the father is obtained in accord with the informed consent provisions of 45 CFR 46 subpart A, except that the father's consent need not be obtained if he is unable to consent because of unavailability, incompetence, or temporary incapacity or the pregnancy resulted from rape or incest.
  • Each individual providing consent must be fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate;
  • For children as defined in 45 CFR 46.402 (a) who are pregnant, assent and permission are obtained in accord with the provisions of 45 CFR 46 subpart D of this part;
  • No inducements, monetary or otherwise, will be offered to terminate a pregnancy;
  • Individuals engaged in the research will have no part in any decisions as to the timing method, or procedures used to terminate a pregnancy; and
  • Individuals engaged in the research will have no part in determining the viability of a neonate.

7.1.2 Research Involving Neonates

Before approving any research involving neonates (defined as newborns), the IRB determines and documents:

  • Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates;
  • Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the neonate; and
  • Individuals engaged in the research will have no part in determining the viability of a neonate

Until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in research covered by this subpart unless the IRB determines that:

  • The research holds out the prospect of enhancing the probability of survival of the neonate to the point of viability, and any risk is the least possible for achieving that objective of the research, or
  • The purpose of the research is the development of important biomedical knowledge which cannot be obtained by other means and there will be no risk to the neonate resulting from the research; and
  • The legally effective informed consent of either parent of the neonate or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, the legally effective informed consent of either parent's legally authorized representative is obtained in accord with 45 CFR 46 Subpart A of this part, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.

After delivery, nonviable neonates may not be involved in research covered by this subpart unless all of the following additional conditions are met:

  • Vital functions of the neonate will not be artificially maintained;
  • The research will not terminate the heartbeat or respiration of the neonate;
  • There will be no added risk to the neonate resulting from the research;
  • The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and The legally effective informed consent of both parents of the neonate is obtained in accord with 45 CFR 46 Subpart A, except that the waiver and alteration provisions of Sec. 46.116 (c ) and (d) do not apply. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable fetus will suffice to meet the requirements of this paragraph, (c ) (5), except that the consent of the father need not be obtained if the pregnancy resulted from rape or incest. The consent of a legally authorized representative of either or both of the parents of a nonviable neonate will not suffice to meet the requirements of this paragraph.

A neonate, after delivery, that has been determined to be viable may be included in research only to the extent permitted by and in accord with the requirements of 45 CFR 46 subpart A and D.

7.2. Additional Protections for Children Involved in Research

With proposed research involving children, the IRB considers the degree of risk to individual subjects and assesses whether the benefits are to the child-subject or to society as a whole.

7.2.1. Types of Reviews

With respect to all research involving children as human subjects, conducted or supported by SHS, the IRB shall conduct an expedited or full review of each research protocol except for the following (which is subject to exempt review):

  1. Research conducted in established or commonly accepted educational settings, normal educational practices, such as (1) research on regular and special education instructional strategies, or (ii) research on the effectiveness or the comparison among instructional techniques, curricula, or classroom management methods.
  2. Research involving the use or educational tests (cognitive, diagnostic, aptitude, achievement,) survey procedures, interview procedures or observation of public behavior (when the investigator does not participate in the activities being observed) unless: (i) information obtained is recorded in such a manner that human subjects can be identified, directly or through identifies linked to the subjects; and (ii) any disclosure of human subjects' responses outside the research could reasonably place the subjects at risk of criminal or civil liability or be damaging to the subjects' financial standing, employability or reputation.
  3. Research involving the collection or study of existing data, documents, recorded, pathological specimens, or diagnostic specimens if these sources are publicly available or if the information is recorded by the investigator is such a manner that human subjects cannot be identified, directly or through identifies linked to the human subjects.
  4. Research and demonstration projects which are conducted by or subject to the approval of the appropriate federal official and which are designed to study, evaluate, or otherwise examine: )i) Public benefit or service programs, (ii) procedures for obtaining benefits or services under those programs, (iii) possible changes in or alternatives to those programs or procedures, or (iv) possible changes in methods or levels or payment for benefits or services under those programs.

7.2.2 Research Not Involving Greater Than Minimal Risk for Children

SHS will conduct or fund research in which the IRB finds that no greater than minimal risk to children is presented, only if the IRB finds that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians.

7.2.3 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.

SHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, only if the IRB finds that:

(a) the risk is justified by the anticipated benefit to the subjects;

(b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and

(c) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth in these policies.

7.2.4 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

SHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject, only if the IRB finds that:

(a) the risk represents a minor increase over minimal risk;

(b) the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;

(c) the intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition; and

(d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians.

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

SHS will conduct or fund research that the IRB does not believe meets the requirements of the sections listed above pertaining to children only if :

(a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and

(b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either:

(1) that the research in fact satisfies the following conditions : (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (ii) the research will be conducted in accordance with sound ethical principles; (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians.

7.2.6 Requirements for permission by parents or guardians and for assent by children.

In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent. In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. This judgment may be made for all children to be involved in research under a particular protocol, or for each child, as the IRB deems appropriate. If the IRB determines that the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research, the assent of the children is not a necessary condition for proceeding with the research. Even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement under circumstances in which consent may be waived in accord with these policies pertaining to children involved in research.

7.2.7 Requirements for Permission by Parents or Guardians

In addition to the determinations required under other applicable sections of this subpart, the IRB shall determine, in accordance with and to the extent that consent is required by these policies, that adequate provisions are made for soliciting the permission of each child's parents or guardian. Where parental permission is to be obtained, the IRB may find that the permission of one parent is sufficient for research to be conducted under these policies.. Where research is covered by these policies and permission is to be obtained from parents, both parents must give their permission unless one parent is deceased, unknown, incompetent, or not reasonably available, or when only one parent has legal responsibility for the care and custody of the child.

7.2.8 Waiver of Consent

In addition to the provisions for waiver contained in the section titled "Waivers or Alterations to Approved Informed Consent Requirements", the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subjects (for example, neglected or abused children), it may waive the consent requirements in Subpart A of this part and paragraph (b) of this section, provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, State, or local law. The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity, status, and condition.

7.2.9 Documentation of Consent

Permission by parents or guardians shall be documented in the same manner and to the extent that is required for an adult research subject. When the IRB determines that assent is required, it also shall determine whether and how assent must be documented.

7.2.10 Wards

Children who are wards of the State or any other agency, institution, or entity can be included in research approved under this section only if such research is:(a) related to their status as wards; or (b) conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards. If the research is approved, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child's participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization.

7.3 Emergency Treatment Research

7.3.1. General

The Board may approve research involving emergency treatment and/or therapies where normal standards of obtaining informed consent are not possible when the IRB (with the concurrence of a licensed physician who is a member of or consultant to the IRB and who is not otherwise participating in the clinical investigation) finds and documents each of the following:

  • The human subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence, which may include evidence obtained through randomized placebo-controlled investigations, is necessary to determine the safety and effectiveness of particular interventions;
  • Obtaining informed consent is not feasible because:
    • The subjects will not be able to give their informed consent as a result of their medical condition;
    • The intervention under investigation must be administered before consent from the subjects' legally authorized representatives is feasible; and
    • There is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation.
  • Participation in the research holds out the prospect of direct benefit to the subjects because:
    • Subjects are facing a life-threatening situation that necessitates intervention;
    • Appropriate animal and other pre-clinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the intervention to provide a direct benefit to the individual subjects; and
    • Risks associated with the investigation are reasonable in relation to what is known about the medical condition of the potential class of subjects, the risks and benefits of standard therapy, if any, and what is known about the risks and benefits of the proposed intervention or activity.
  • The clinical investigation could not practicably be carried out without the waiver.
  • The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legally authorized representative for each subject within that window of time and, if feasible, to asking the legally authorized representative contacted for consent within that window rather than proceeding without consent.
  • The investigator will summarize efforts made to contact legally authorized representatives and make this information available to the IRB at the time of continuing review.
  • The IRB has reviewed and approved informed consent procedures and an informed consent document consistent with informed consent requirements described above;
  • These procedures and the informed consent document are to be used with subjects or their legally authorized representatives in situations where use of such procedures and documents is feasible.
  • The IRB has reviewed and approved procedures and information to be used when providing an opportunity for a family member to object to a subject's participation in the clinical investigation described below;

7.3.2 Additional Protections in Emergency Research

Additional protections of the rights and welfare of the subjects will be provided, including, at least:

  • Consultation (including, where appropriate, consultation carried out by the IRB) with representatives of the communities in which the clinical investigation will be conducted and from which the subjects will be drawn;
  • Public disclosure to the communities in which the clinical investigation will be conducted and from which the subjects will be drawn, prior to initiation of the clinical investigation, of plans for the investigation and its risks and expected benefits;
  • Public disclosure of sufficient information following completion of the clinical investigation to apprise the community and researchers of the study, including the demographic characteristics of the research population, and its results; of an independent data monitoring committee to exercise oversight of the clinical investigation; and
  • If obtaining informed consent is not feasible and a legally authorized representative is not reasonably available, the investigator has committed, if feasible, to attempting to contact within the therapeutic window the subject's family member who is not a legally authorized representative, and asking whether he or she objects to the subject's participation in the clinical investigation. The investigator will summarize efforts made to contact family members and make this information available to the IRB at the time of continuing review.

7.3.3 Post Enrollment Consent

The Principal Investigator must inform, at the earliest feasible opportunity, each subject, or if the subject remains incapacitated, a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member, of the subject's inclusion in the clinical investigation, the details of the investigation and other information contained in the informed consent document. The investigator must also inform the subject, or if the subject remains incapacitated, a legally authorized representative of the subject, or if such a representative is not reasonably available, a family member, that he or she may discontinue the subject's participation at any time without penalty or loss of benefits to which the subject is otherwise entitled. If a legally authorized representative or family member is told about the clinical investigation and the subject's condition improves, the subject is also to be informed as soon as feasible. If a subject is entered into a clinical investigation with waived consent and the subject dies before a legally authorized representative or family member can be contacted, information about the clinical investigation is to be provided to the subject's legally authorized representative or family member, if feasible.

7.3.4. Separate FDA Applications

For emergency treatment research utilizing a drug or medical device, protocols involving an exception to the informed consent requirement under this section must be performed under a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly identifies such protocols that may include subjects who are unable to consent. The submission of those protocols in a separate IND/IDE is required even if an IND for the same drug product or an IDE for the same device already exists.

7.3.5. Documentation of Informed Consent (Emergency Research)

The IRB determinations and documentation required by this section are to be retained by the IRB for at least 3 years after completion of the clinical investigation, and the records shall be accessible for inspection and copying by FDA in accordance with 21 CFR 56.115(b).

7.3.6 IDE/ IND Requirements for Emergency Research Protocols (Informed Consent Exceptions)

Protocols involving an exception to the informed consent requirement under this section must be performed under a separate investigational new drug application (IND) or investigational device exemption (IDE) that clearly identifies such protocols as protocols that may include subjects who are unable to consent. The submission of those protocols in a separate IND/IDE is required even if an IND for the same drug product or an IDE for the same device already exists. Applications for investigations under this section may not be submitted as amendments under 21 CFR 312.30 or 812.35.

7.3.7 IRB Rulings Against Emergency Research

If an IRB determines that it cannot approve a clinical investigation because the investigation does not meet the criteria in the exception provided above or because of other relevant ethical concerns, the IRB must document its findings and provide these findings promptly in writing to the clinical investigator and to the sponsor of the clinical investigation. The sponsor of the clinical investigation must promptly disclose this information to FDA and to the sponsor's clinical investigators who are participating or are asked to participate in this or a substantially equivalent clinical investigation of the sponsor, and to other IRB's that have been, or are, asked to review this or a substantially equivalent investigation by that sponsor.

7.4 Protection for Research Involving Prisoners as Subjects

The provisions of this section govern all research conducted at SHS involving any individual involuntarily confined or detained in a penal institution as subjects. The IRB will require the following additional safeguards for the protection of prisoners involved in research:

  • A majority of the IRB (exclusive of prisoner members) shall have no association with the prison (s) involved, apart from their membership on the IRB.
  • At least one member of the IRB shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity. If a particular research project is reviewed by more than one IRB, only one IRB must satisfy this requirement.
  • The IRB may enter into a cooperative agreement with another IRB meeting the criteria to satisfy the requirements listed above.

7.5 Additional Guidelines for the Protection of Prisoners Involved in Research

In addition to the all other responsibilities prescribed for the IRB, the IRB shall review research covered by this subpart and approve such research only if it finds that the research under review represent one of the categories of research:

  1. Study of the possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
  2. Study of prisons as institutional structures or of prisoners as incarcerated persons, provided the study presents no more than minimal risk and no more than inconvenience to the subjects;
  3. Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and the research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that the study may proceed only after the Secretary ahs consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of his intent to approve such research; or
  4. Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject. In cases which those studies require the assignment of prisoners in a manner consistent with protocols approved by the IRB to control groups which may not benefit from the research, the study may proceed only after the Secretary has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the intent to approve such research. In addition:
    • any possible advantages accruing to the prisoner through his or her participation in the research, when compared to 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;
    • the risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers;
    • procedures for the selection of 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 Board 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;
    • the information is presented in language which is understandable to the subject population;
    • adequate assurance exists that parole boards will not take into account a prisoners 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; and
    • where the Board 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 prisoners, sentences, and for informing participants of this fact.

7.5.1.1 Federally Funded Research

Where the research on prisoners is to be funded by the Department of Health and Human Services or another federal agency (as may be subject to DHHS oversight) the IRB must certify to the Secretary of Health and Human Services (in such provisions of 45 CDR Subpart C and approval of said research must be made contingent upon determination of the Secretary that it satisfies the requirements of 8.4.2. The IRB shall carry out such other duties as may be assigned by the Secretary.