Obtaining consent from potential subjects is an ongoing process. The process of informed consent is fundamental to insuring the continuous and adequate disclosure of research risks and benefits. Informed consent begins with the initial presentation of a research activity to a prospective human subject by the investigator (or a member of the study team) and continues through the end of the research activity and the closing of the research study. It involves a thorough oral briefing of each potential subject by the researcher, including all informed consent elements per 45 CFR 46.116 (below), especially a discussion of any potential risks and potential loss of privacy; efforts to ensure that each subject has fully understood what has been agreed to and has had all questions answered; and subject signature on a consent form documenting that the subject has participated in the process of informed consent and has agreed to participate in the study.
Signature on a consent form does not by itself constitute informed consent; nor does the consent process end with the signing of the informed consent document. Research is an on-going process, which involves the constant re-evaluation of current information and procedures. Therefore, investigators are ethically obligated to keep subjects apprised of issues related to their participation in the study as appropriate. Any new information or changes in procedures that affect the participants should be presented to them in writing; in most cases it will involve the signing of a new consent form or a revision of the original form.
Federal regulations at 45 CFR 46.116(a), state that the following information must be provided to each potential participant in a research project:
1. a statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject’s participation, a description of the procedures to be followed, and identification of any procedures which are experimental;
2. a description of any reasonably foreseeable risks or discomforts to the subject;
3. a description of any benefits to the subject or to others which may reasonably be expected from the research;
4. a disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject;
5. a statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained;
6. for research involving more than minimal risk, an explanation as to whether any compensation or any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained;
7. an explanation of whom to contact for answers to pertinent questions about the research and research subjects’ rights, and whom to contact in the event of a research-related injury to the subject; and
8. a statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.
The regulations at 45 CFR 46.116(b) further require that one or more of the following additional information be provided to each subject, where appropriate:
1. a statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable;
2. anticipated circumstances under which the subject’s participation may be terminated by the investigator without regard to the subject’s consent;
3. any additional costs to the subject that may result from participation in the research;
4. the consequences of a subject’s decision to withdraw from the research and procedures for orderly termination of participation by the subject;
5. a statement that significant new findings developed during the course of the research which may relate to the subject’s willingness to continue participation will be provided to the subject; and
6. the approximate number of subjects involved (or to be involved) in the study.
Prior to admitting a subject into a research study, a researcher must obtain the informed consent of the individual involved. Accordingly, no researcher may involve a human being as a subject in a research study unless the researcher has obtained the legally effective written informed consent of the subject or the subject’s legally authorized representative (unless the IRB has specifically waived consent and/or written documentation of consent; see §§4.3, 4.4 below).
Obtaining informed consent from special populations such as children and individuals with diminished capacity to consent may require additional procedures. In addition to parental permission, assent is to be sought from minors in a manner commensurate with their maturity and ability to understand and to use language. Typically, a minor may not be entered into a study without giving assent (see §4.5.5 below).
The requirements for informed consent will depend on the nature of the research protocol. There are four variations of informed consent process and documentation requirements:
· with children, this would include assent of the minor and consent from one or two parents/guardians;
· use of proxy consent, including a surrogate for Health-care decisions (per HRS §327E-5);
· request for emergency waiver of consent, when applicable.
4. a request for waiver of some or all elements of informed consent in non-emergency situations.
Note: 45 CFR 46.116 prohibits any exculpatory language in informed consent through which the subject is made to waive, or appear to waive, any of the subject’s legal rights.
Note: Public Health Services (PHS) policy requires that where HIV testing is conducted or supported by the PHS, individuals whose test results are associated with personal identifiers must be informed of their own test results and provided the opportunity to receive appropriate counseling unless the situation calls for an exception as set forth in the Policy (see OPRR reports 10 June, 1988 at <http://ohrp.osophs.dhhs.gov/humansubjects/guidance/hsdc88jun.htm>). This procedure should be described in the informed consent document.
In most circumstances, a written consent form is required; only the current CHS-approved consent document may be used. The investigator shall give either the subject or the representative adequate opportunity to read it and ask questions before it is signed. Per 45 CFR 46.116, when necessary, the written consent form may be read to the subject or the subject’s legally authorized representative. The original consent document should be maintained by the PI. A copy of the signed consent form must be given to the subject or subject’s representative with additional copies placed in the subject’s medical record, if applicable, and provided to others (i.e., pharmacy, sponsor, etc.), as required.
The written consent form should be typed in 12-point font and written in language easily understood by a person having no greater than seventh-grade level reading skills.
There are special consent requirements for research with individuals under the age of 18, unless the individual is pregnant or an emancipated minor. A full discussion of parental consent and child assent is provided below at §4.5.5.
Per 45 CFR 46.116, special note must be made that the procedures for enrolling subjects minimize the possibility of coercion or undue influence.
Note: Standard surgical consent documents rarely include all the elements required under 45 CFR 46.116. Reliance on such documents for research generally requires formal waiver of consent requirements (see §4.4 below).
In 1997, the DHHS and FDA provided a narrow exception to the standard requirements for obtaining informed consent from each subject or his/her legal representative prior to initiation of an experimental intervention. These Federal regulations allow the IRB to approve a limited class of research activities involving human subjects in need of emergency medical intervention, but who are unable to consent because of their life-threatening medical condition. The stated intent of the regulation is to allow research on life-threatening conditions for which available treatments are unproven or unsatisfactory and which would ordinarily require written consent in specific instances or populations and where it is not possible to obtain consent while establishing additional protections to provide for safe and ethical studies and protect the rights of vulnerable populations of subjects.
Use of this provision requires special justification, community consultation, the preparation of a consent document, the consenting of a subject or the subject’s proxy as soon as feasible, and other unique considerations. The CHS will review requests to waive consent in certain emergency research on a case-by-case basis.
Per FDA regulations, in order to approve an emergency research consent waiver study, the IRB must find and document that:
1. subjects are in a life-threatening situation, available treatments are unproven or unsatisfactory and collection of scientific evidence is necessary;
2. obtaining informed consent is not feasible because:
a. the medical condition precludes consent;
b. there is no time to get consent from a legally authorized representative;
c. prospective identity of likely subjects is not reasonable.
3. There is a prospect of direct benefits to the study subjects because:
a. the life-threatening situation necessitates treatment;
b. data support a potential for direct benefit to individual subjects;
c. the risk/benefit ratio of both standard and proposed treatments are reasonable.
4. A waiver is needed to carry out the study;
5. the plan defines a therapeutic window, during which the investigator will seek consent rather than starting without consent (a summary of efforts will be given to the IRB at the time of Continuing review);
6. the IRB must review and approve the consent procedures, consent document(s), and procedures for family member objection;
7. there are additional protections, including at least:
a. consultation with community representatives;
b. public disclosure of study results;
c. assure the establishment of an independent Data Monitoring Committee;
d. any objections of family members are summarized for Continuing review.
8. There are procedures in place to inform subject and/or subject’s family at the earliest feasible opportunity of the subject’s inclusion in the study (participation may be discontinued);
9. there is a separate IND or IDE, even for marketed products (see §§5.2 and 5.3 of this manual);
10. any IRB disapproval must be documented in writing and sent to the PI and the sponsor of the investigation.
DHHS regulations for the protection of human subjects do not permit research activities to be started, even in emergencies, without prior IRB review and approval of a research protocol and applicable consent forms. Thus, unless the IRB has appropriately waived the informed consent requirements, if a patient is treated via this emergency use mechanism, then the patient, and any data derived from the treatment of that patient, may not be used for the evaluation of the product since the patient did not sign an informed consent document.
HHS regulations at 45 CFR 46.117(b)(2) permit oral presentation of informed consent information in conjunction with a short form written informed consent document (stating that the elements of consent have been presented orally) and a written summary of what is presented orally.
All protocols requesting such procedures are carefully reviewed by the IRB to determine whether the short form process and documentation will suffice.
Per 45 CFR 46.117, the short form written consent is a document stating that the elements of informed consent (as outlined in §4 of this manual) have been presented orally to the subject or the subject’s legally authorized representative. When this method is used, there must be a witness to the oral presentation. Also, the IRB must approve a written summary or script of what is to be said to the subject or the representative. Only the short form itself is to be signed by the subject or the representative. However, the witness should sign both the short form and a copy of the summary, and the person actually obtaining consent should sign a copy of the summary. A copy of the summary should be given to the subject or the representative, in addition to a copy of the “short form.” When appropriate, the obtaining of the short form consent must also be documented in the subject’s medical record by the person who obtained the consent; the PI should maintain the original short form.
When this procedure is used with subjects who do not speak English, (i) the oral presentation and the short form written informed consent document should be in a language understandable to the subject; (ii) the IRB-approved English language informed consent document may serve as the summary; and (iii) the witness should be fluent in both English and the language of the subject.
Under certain conditions, the requirement to provide documentation of the informed consent process can be waived. In this process, the investigator obtains informed consent through the use of an oral consent script. Similar to a written consent, the script should include information regarding the nature and duration, risks and benefits, alternatives, and cost to subjects. The subject will either verbally agree or not agree to participate in the study. Investigators are not required to secure written documentation of consent obtained orally.
Per 45 CFR 46.117(c), in order to qualify for oral consent, one of the following criteria must apply:
1. The only record linking the subject and the research would be the consent document and the principal risk would be the potential harm resulting from a breach of confidentiality. Each subject will be asked whether the subject wants documentation linking the subject with the research, and the subject’s wishes will govern.
2. The research presents no more than minimal risk of harm to subjects and involves no procedures for which written consent is normally required outside of the research context.
There are circumstances in which the IRB may consider a waiver of the requirements of informed consent. Per 45 CFR 46.116(c), the IRB may alter or waive the requirement to obtain informed consent only if the IRB finds and documents in the CHS’s file for the study (Expedited Review) or the IRB meeting minutes (Full Review) that:
1. the research or demonstration is to be conducted by or subject to the approval of state or local government officials and is designed to study, evaluate, or otherwise examine:
i. public benefit of service programs;
ii. procedures for obtaining benefits or services under those programs;
iii. possible changes in or alternatives to those programs or procedures; or
iv. possible changes in methods or levels of payment for benefits or services under those programs, and
2. the research could not practicably be carried out without the waiver or alteration.
When the IRB authorizes a waiver of consent, this waiver does not apply to any other consent that may be required by any other committee or institutional procedure. To request approval for waiver of consent, the investigator should indicate the request on the CHS Application Form and provide a written justification addressing each of the four points listed below. Per 45 CFR46.116(d), the IRB may waive the requirements to obtain informed consent provided the IRB finds and documents that:
1. the research presents no more than minimal risk of harm to subjects;
2. the waiver or alteration will 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. whenever appropriate, the subjects will be provided with additional pertinent information after participation.
Appropriate procedures for maintenance of confidentiality should be described in the protocol.
Whenever proposed research subjects may be vulnerable to injury, coercion or undue influence, the PI must include additional safeguards in the consent process and the study protocol to protect the potential subject’s rights and welfare.
Universities, and the association of investigators with them, provide investigators with a ready pool of research subjects: students. The problem with student participation in research conducted at the UH is that their agreement to participate may not be able to be freely given. Students may volunteer to participate out of a belief that doing so will place them in good favor with faculty (e.g., that participating will result in receiving better grades, recommendations, employment, or the like), or that failure to participate will negatively affect their relationship with the investigator or faculty in general (i.e., by seeming “uncooperative,” not part of the scientific community). Prohibiting all student participation in research, however, would clearly be an overprotective reaction. An alternative way to protect against coercion is to advertise for subjects generally (e.g., through notices posted in the school or department) rather than recruit individual students directly. As with any research involving a potentially vulnerable subject population, the CHS will pay special attention to the potential for coercion or undue influence and consider ways in which the possibility of exploitation can be reduced or eliminated. Particular scrutiny will be made in studies where the PI or researchers are using their own students as subjects.
Requiring participation in research for course credit (or extra credit) is also controversial, though common in the social and behavioral sciences. Students in beginning psychology courses, for instance, might be required to serve as subjects for a given number of hours of research or in a given number of research projects; or they might be given the option of participating for additional grade credit. In either case, students should be afforded a non-research alternative to complete course requirements or earn extra credit. This alternative should be no less attractive (e.g., in time or effort) than the research opportunity. Another concern raised by the involvement of students as subjects is confidentiality. As with research involving human subjects generally, the CHS must be made aware that research involving the collection of data on sensitive subjects such as mental health, sexual activity, or the use of illicit drugs or alcohol presents risks to subjects of which they should be made aware and from which they should be protected, to the greatest extent possible.
The issues with respect to employees as research subjects are essentially identical to those involving students as research subjects: coercion or undue influence, and confidentiality. As student participation raises questions of the ability to exercise free choice because of the possibility that grades or other important factors will be affected by decisions to participate, employee research programs raise the possibility that the decision will affect performance evaluation or job advancement. It may also be difficult to maintain the confidentiality of personal medical information or research data when the subjects are also employees.
The predominant ethical concern in research involving individuals with psychiatric, cognitive, or developmental disorders, or who are substance abusers is that their disorders may compromise their decisional capacity, that is, their capacity to understand the information presented and their ability to make a reasoned decision about participation. Many individuals with disabilities affecting their reasoning powers may be residents of institutions responsible for their total care and treatment. The impact of institutionalization may further compromise their ability to exercise free choice (voluntariness). These concerns apply both to voluntary patients and those committed involuntarily. It is important to protect the privacy of all subjects and the confidentiality of information gathered in research exploring emotionally sensitive topics.
It is now generally accepted that research involving persons whose autonomy is compromised by disability or restraints on their personal freedom should bear some direct relationship to their condition or circumstances. Persons who are institutionalized, particularly if disabled, should not be chosen for studies that bear no relations to their situation just because it would be convenient for the researcher.
As a general rule the CHS requires that all adults, regardless of their diagnosis or condition, should be presumed competent to consent unless there is evidence of serious mental disability that would impair reasoning or judgment. Even those who do have a diagnosed mental disorder may be decisionally capacitated, and perfectly able to understand the matter of being a research volunteer, and quite capable of consenting to or refusing participation. Mental disability alone should not disqualify a person from consenting to participate in research; rather, there should be specific evidence of individuals’ incapacity to understand and to make a choice before they are deemed unable to consent.
For individuals who may have diminished mental capacity there must be an assessment of the subject’s capacity to consent to participate prior to enrolling the subject in the study. For all subjects in studies involving individuals with psychiatric illness, and for any other subject in any other study for whom there is diminished mental capacity or a question of diminished capacity, the Committee may request that the assessment should be undertaken by a qualified mental health professional not associated with the study and whose professional training and credentials are suitable given the nature of the subject’s illness and the nature of the study. This individual must be completely independent from the study and should not appear as an author on any published paper reporting on the study, as that might lead to the appearance of conflict. The protocol must indicate how the assessment of capacity will be undertaken. Factors to be considered in assessing capacity include:
In the event the subject lacks the capacity to consent to participate, consent can only be given by an individual legally authorized to consent on behalf of the subject.
If there is a likelihood that a subject’s capacity may become impaired during the course of a study, then the specific mechanisms for monitoring the subject(s) to determine if there is a decrease in capacity must be detailed in the protocol and/or the consent form.
Persons formally adjudged incompetent have a court-appointed guardian who must be consulted and who can give consent on their behalf. Officials of the institution in which incompetent patients reside are not generally considered appropriate, since their supervisory duties may give rise to conflicting interests and loyalties. Family members or others financially responsible for the patient may also be subject to conflicting interests because of financial pressures, emotional distancing, or other ambivalent feelings common in such circumstances; use of a subject advocate is recommended.
This guidance (which is based on the Federal Regulations at 45 CFR 46 Subpart B) applies to all research, development, and related activities involving: (i) the fetus, (ii) pregnant women, and (iii) human in vitro fertilization. The requirements regarding these subjects are in addition to those imposed under other CHS policies.
Research involving women who are or may become pregnant should receive special attention from investigators because of women’s additional health concerns during pregnancy and because of the need to avoid unnecessary risk to the fetus. Further, in the case of a pregnant woman, the investigator must consider when the informed consent of the father is required for the research to take place. Special attention is justified because of the involvement of a third party (the fetus) who may be affected but cannot give consent. Procedural protections beyond the basic requirements for protecting human subjects are prescribed in Federal regulations for research involving pregnant women.
· Additional Requirements For Activities Involving Fetuses, Pregnant Women, or Human in Vitro Fertilization.
In addition to all other requirements for approval, the IRB must determine that:
1. adequate consideration has been given to the manner in which potential subjects will be selected; and
2. adequate provision has been made by the investigator for monitoring the actual informed consent process (e.g., through such mechanisms, when appropriate, as participation by the IRB or subject advocates in (i) overseeing the actual process by which individual consents are secured either by approving induction of each individual into the activity or verifying, perhaps through sampling, that approved procedures for induction of individuals into the activity are being followed; and (ii) monitoring the progress of the activity and intervening as necessary through such steps as visits to the activity site and continuing evaluation to determine if any unanticipated risks have arisen).
· Activities Directed Toward Pregnant Women as Subjects.
In general, unless the research falls within one of the Exempt categories at 45 CFR 46.101(b)(1-6) (outlined at §3.1.1 of this manual), no pregnant woman may be involved as a research subject unless: (1) the purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus is minimal.
A. Parental Consent.
An activity permitted under the above mentioned criteria may be conducted only if the mother and father are legally competent and have both given their informed consent after having been fully informed regarding possible impact on the fetus, except that the father’s informed consent need not be secured if:
i. the purpose of the activity is to meet the health needs of the mother;
ii. his identity or whereabouts cannot reasonably be ascertained;
iii. he is not reasonably available; or
iv. the pregnancy resulted from rape.
· Activities Directed Toward Fetuses in Utero as Subjects.
No fetus in utero may be involved as a subject in any research activity unless the IRB determines either:
1. the purpose of the activity is to meet the health needs of the particular fetus and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or
2. the risk to the fetus imposed by the research is minimal and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means.
A. Parental Consent.
If such an activity is approved, it may be conducted only if the mother and father are legally competent and have both given their informed consent, except that the father’s consent need not be secured if:
i. his identity or whereabouts cannot reasonably be ascertained;
ii. he is not reasonably available; or
iii. the pregnancy resulted from rape.
· Activities Directed Toward Fetuses ex Utero, Including Nonviable Fetuses, as Subjects
Until it has been ascertained whether or not a fetus ex utero is viable, a fetus ex utero may not be involved as a subject unless:
1. there will be no added risk to the fetus resulting from the activity, and the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means, or
2. the purpose of the activity is to enhance the possibility of survival of the particular fetus to the point of viability.
A. Nonviable Fetuses.
No nonviable fetus may be involved as a subject unless:
i. vital functions of the fetus will not be artificially maintained,
ii. experimental activities which of themselves would terminate the heartbeat or respiration of the fetus will not be employed, and
iii. the purpose of the activity is the development of important biomedical knowledge which cannot be obtained by other means.
B. Parental Consent.
Activities directed toward fetuses ex utero, including nonviable fetuses, as subjects may be conducted only if the mother and father are legally competent and have both given their informed consent, except that the father’s informed consent need not be secured if:
i. his identity or whereabouts cannot reasonably be ascertained;
ii. he is not reasonably available; or
iii. the pregnancy resulted from rape.
· Activities Involving the Dead Fetus, Fetal Material, or the Placenta.
Per section 498A of the Public Health Services Act (42 USC 289g-1), the DHHS may conduct or support research on the transplantation of human fetal tissue (obtained pursuant to a spontaneous or induced abortion, or a stillbirth) for therapeutic purposes only if a number of provisions are met. PIs should refer to the statute (available at <http://ohrp.osophs.dhhs.gov/humansubjects/guidance/publiclaw103-43.htm>) for more information on the statutory requirements for research on transplantation of fetal tissue.
All activities involving the dead fetus, macerated fetal material, or cells, tissue, or organs excised from a dead fetus shall be conducted only in accordance with any applicable State laws regarding such activities.
· Modification or Waiver of Specific Requirements.
Upon the request of the investigator (with the approval of the IRB), the Secretary of the DHHS may modify or waive any of the above requirements of this Policy.
· Studies in Which Pregnancy is Coincidental to Subject Selection
Any study in which women of childbearing potential are possible subjects may inadvertently include pregnant women. Federal regulations require that, when appropriate, subjects be provided a statement that the particular treatment or procedure may involve risks to the subject (or to the embryo or fetus, if the subject is or may become pregnant) which are currently unforeseeable as part of the informed consent process.
In some studies, the investigator may need to ensure that nonpregnant subjects are advised to avoid pregnancy or nursing for a time during or following the research. Furthermore, where appropriate, subjects should be advised to notify the investigator immediately should they become pregnant. In some instances there may be potential risk sufficient to justify requiring that pregnant women either be specifically excluded from the research or studied separately.
In general, non-Exempt research involving children (i.e., under the age of 18) requires the use of written informed consent. Consent to participate must be provided by at least one parent or guardian; in instances where the research presents more than minimal risk and/or provides no direct benefit to the subject, consent of both parents may be required. In addition, assent of the participating child typically must be obtained for all children with the capacity to understand the research, its risks and benefits, and the alternatives to the research.
The IRB may approve research involving children only if special provisions are met and the research falls into one of the following four categories:
1. Research Not Involving More Than Minimal Risk
When the IRB finds that no greater than minimal risk to children is presented, the IRB may approve the proposal 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.
2. Research Involving Greater than Minimal Risk but Presenting the Prospect of Direct Benefit to the Individual Subjects.
If the IRB finds that more than minimal risk to children is presented by an intervention or procedure but that the intervention or procedure 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, the IRB may approve the research only if the IRB finds that:
i. the risk is justified by the anticipated benefit to the subjects;
ii. 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
iii. adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians, as set forth below.
3. 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.
If 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, the IRB may approve the research only if the IRB finds that:
i. the risk represents a minor increase over minimal risk;
ii. 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;
iii. 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
iv. adequate provisions are made for soliciting assent of the children and permission of their parents or guardians, as set forth below.
4. Research Not Otherwise Approvable Which Presents an Opportunity to Understand, Prevent, or Alleviate a Serious Problem Affecting the Health or Welfare of Children.
If the IRB does not believe the research proposal meets any of the requirements set forth above, it may still approve the application, but only if:
i. 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
ii. the Secretary of the DHHS, 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:
a. that the research in fact satisfies one of the conditions set forth above, or
b. the following: (1) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; (2) the research will be conducted in accordance with sound ethical principles; and (3) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §§ 4.5.5.1 and 4.5.5.4 below.
Assent should be obtained for children ages 7-17. Under Hawaii law, the legal age of consent is 18, at which point a person is considered an adult and can legally consent to medical treatment or services and to participate in a research study.
The regulations specify certain criteria in determining whether the children in a research activity are capable of giving assent. These criteria include the children’s age, maturity level, psychological state, and the complexity of the proposed study procedure(s). Another factor to consider is the degree of risk involved in the procedures. The researcher should consider these factors in designing the study consent/assent procedures.
Assent is not required if the CHS determines that
1. the capability of some or all of the children is so limited that they cannot reasonably be consulted;
2. 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.
Additionally, in such circumstances a child’s dissent, which should normally be respected, may be overruled by the child’s parents, at the IRB’s discretion. When research involves the provision of experimental therapies for life-threatening diseases such as cancer, however, the IRB should be sensitive to the fact that parents may wish to try anything, even when the likelihood of success is marginal and the probability of extreme discomfort is high. Should the child not wish to undertake such experimental therapy, difficult decisions may have to be made. In general, if the child is a mature adolescent and death is imminent, the child’s wishes should be respected.
Even if the child is capable of assent, the CHS may waive the assent requirement in the same manner that consent may be waived (see §4.4 of this manual). This determination must be made by the CHS, not the researcher.
Along with a child’s assent, parental permission must also be obtained when children are involved in a research activity. The following rules apply:
1. The child’s assent and at least one parent’s/guardian’s permission is required when:
2. The child’s assent and both parents’/guardian’s permission is required when:
When permission must be obtained from both parents, both parents must give 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. The IRB may waive the requirement for permission if it determines that it is not a reasonable requirement to protect the subjects, provided an appropriate substitute mechanism for protecting the children is instituted.
Parental consent can be waived by the IRB if informed consent could also be waived in accordance with 45 CFR 46.116(d). As outlined in §4.4 above, in order to waive parental permission, the IRB must find and document that:
1. the research involves no more than minimal risk to the subjects;
2. the waiver or alteration will 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. whenever appropriate, the subjects will be provided with additional pertinent information after participation.
Per 45 CFR 46.408(c), parental consent may also be waived under the following circumstances:
In addition to the provisions for waiver contained in [Subpart A of 45 CFR 46], if 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 [45 CFR 46] and paragraph (b) of [section 46.408], 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.
The best interests of the child are the primary concern. In any event, parental permission should be waived only under extraordinary circumstances.
It should be noted that, while 45 CFR 46 Subpart D makes allowances for certain extraordinary circumstances wherein waiver of the requirement for parental permission may be allowed, FDA regulations at 21 CFR 50 Subpart D specifically require parental permission in all cases. In a situation where two Federal regulations conflict, the CHS will always follow the more conservative; accordingly, per 21 CFR 50 Subpart D, for any study under the aegis of the FDA, there are no cases wherein the requirement for parental permission for research with children may be waived by the CHS.
It should further be noted that, under Hawaii State law, (Chapter 577A-2 of the Hawaii Revised Statutes), parental permission is not required when a minor (defined at 577A-1 as being from the age of 14 to 17 inclusive), seeks medical treatment or services for pregnancy, venereal disease or family planning services:
“a female minor who is, or professes to be pregnant, or a minor who is, or professes to be afflicted with a venereal disease, or a minor seeking family planning services shall be deemed to have, and shall have the same legal capacity to act, and the same legal obligations with regard to the giving of such consent […], as a person of full legal age and capacity.”
Assent may not be required in situations where 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 child(ren) and is available only in the context of the research. The IRB will make the final determination whether either of these situations is applicable.
a. A written explanation to the child of the research procedures and any risks involved. This explanation must be appropriate to the child’s age, experience, maturity, and condition. The child will acknowledge by signing this document.
b. A verbal explanation to the child of the research procedures and any risks involved. This verbal explanation must be evidenced by a written summary of the presentation. The child may acknowledge by signing the written summary or can sign the consent document which was signed by the parent/guardian. The minor’s assent section should be separate from the other signatures and should include language indicating an agreement or willingness to participate.
I understand that this is a research study. The research procedures have been explained to me. I have been told about what I will do or what will happen to me. I agree to be a part of this study.
Or (suggested Cancer Center language):
It is my choice to agree to take part in this study.
· Schools and Childcare Settings
CHS policy regarding non-Exempt research to be conducted in schools, both public and private, which involves minor students, requires the following:
· Other Organized Children’s Activities
Generally, the requirements applicable to research in schools are also applicable to other organized children’s activities such as sports and recreational activities. The researcher should provide a clear explanation as to why this particular subject group is necessary to the research. Selection of a particular subject group because it is readily accessible or to facilitate research are not adequate selection criteria.
Individuals who are wards of the State or any other agency, institution, or entity can be included in research if:
In addition, the research must be:
Note: Research that involves greater than minimal risk which offers a direct benefit to the individual participant should not include wards.
If the IRB approves research involving wards, the IRB may appoint an advocate for the ward(s), who, in addition to any other person legally acting on behalf of the ward(s), will act as an advocate on behalf of the ward(s) for the duration of participation in the research project. This person should not be associated in any way with the specific research project, the researcher(s), or the guardian organization. This person may be a member of the CHS who will work closely with the researcher and act in the best interests of the ward(s). The IRB will notify the researcher of such an appointment as a condition of approval of the research.
Special issues arise where subjects do not speak or read English, and where the subject’s native language is not written.
Per 45 CFR 46.116, in cases where subjects do not speak or read English, informed consent information must be presented “in language understandable to the subject,” and in writing. Whenever possible, documents should be written in the subject’s preferred language and such that all the elements necessary for legally effective informed consent are presented. Where an oral presentation of informed consent information is used with subjects who do not speak or read English,
1. the oral presentation and the short form written document should be in a language readily understandable to subjects; and
2. the English-language informed consent document approved by the IRB may serve as the summary.
At the time of consent:
1. the short form document should be signed by the subject (or the subject’s legally authorized representative);
2. the summary (i.e., the English language informed consent document) should be signed by the person obtaining consent as authorized in the study; and
3. the short form document and the summary should be signed by the witness.
When the person obtaining consent is assisted by a translator, the translator may serve as the witness to the consent process. The researcher should submit to the IRB for review all foreign language versions of the short form document and any other translated documents presented to subjects. The IRB may review these documents with outside experts to ensure that translation is appropriate. Expedited review of these versions is acceptable if the study, the full English language informed consent document, and the English version of the short form document have already been approved by the Full IRB.
As some of the world’s languages are not written, the IRB may review research involving subjects whose native language is only spoken. Per 45 CFR 46.116, in these cases, informed consent information must be presented “in language understandable to the subject.” When an oral presentation of informed consent information is used with subjects whose native language is not written,
1. the oral presentation should be in a language readily understandable to subjects; and
2. the English-language informed consent document approved by the IRB may serve as the summary.
At the time of consent, the IRB may also require that
1. the summary (i.e., the English language informed consent document) should be signed by the person obtaining consent as authorized in the study; and
2. the summary should be signed by the witness.
When the person obtaining consent is assisted by a translator, the translator may serve as the witness to the consent process. The researcher must submit to the IRB for review all English language versions of information presented to subjects.
The IRB may approve research involving prisoners only if the following special provisions are met:
· When Subjects Become Prisoners During Research Protocol
If a subject becomes a prisoner after enrollment in research, the investigator is responsible for reporting in writing this situation to the IRB immediately. Upon its review, the IRB can either (i) approve the involvement of the prisoner-subject in the research in accordance with this policy or (ii) determine that this subject must be withdrawn from the research.
· Specific Findings of IRB Required to Approve Research
Per 45 CFR 46.305, when the IRB is reviewing a protocol in which a prisoner is a subject, the IRB Committee must make seven findings as follows:
1. The research under review represents one of the following categories of research (from 456 CFR 46.306(a)(2)):
A. a 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;
B. a study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the subjects;
C. research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on hepatitis which is much more prevalent in prisons than elsewhere; and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults); or
D. research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the subject.
2. 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;
3. The risks involved in the research are commensurate with risks that would be accepted by nonprisoner volunteers;
4. 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 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;
5. The information is presented in language which is understandable to the subject population;
6. 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; and
7. 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 prisoners’ sentences, and for informing participants of this fact.
NOTE: The Secretary of HHS has waived (at Federal Register 68:119, 36929) the applicability of 45 CFR 46.305(a)(1) and 46.306(a)(2) for certain types of epidemiologic research conducted or supported by the DHHS
1. in which the sole purposes are:
i. to describe the prevalence or incidence of a disease by identifying all cases, or
ii. to study potential risk factor associations for a disease, and
2. where the institution responsible for the conduct of the research (i.e., the CHS) certifies to the OHRP that: an IRB approved the research and fulfilled its duties under 45 CFR 46.305(a)(2)-(7) and determined and documented that
i. the research presents no more than minimal risk and no more than inconvenience to the prisoner-subjects, and
ii. prisoners are not a particular focus of the research,
· Permitted Research Involving Prisoners
For research conducted or supported by the DHHS to involve prisoners, two actions must occur:
1. the IRB must certify to the OHRP that it has reviewed and approved the research under the Federal regulations;
2. the OHRP must determine that the proposed research falls within one of the categories of permissible research described above.
If an investigator wishes to engage in non-DHHS-supported research, such certification is not required. However, the IRB may apply the standards of the Federal regulations in reviewing the research.
· Prisoners Who Are Minors
When a prisoner is also a minor (e.g., an adolescent detained in a juvenile detention facility as a prisoner) the special protections regarding children in research (as outlined in §4.5.5 above) will also apply.
· Federal Bureau of Prisons
The Federal Bureau of Prisons places special restrictions on research that takes place within the Bureau of Prisons. Investigators should review the regulations at 28 CFR 512 (<http://www.access.gpo.gov/nara/cfr/waisidx_02/28cfr512_02.html>) when considering such research.
Hawaii is a unique locale for carrying out research on human subjects in part because of the multiple different cultures represented in our islands. In the interest of justice —through equity in subject selection— the CHS may consider requests for waiver, or modification of informed consent requirements when the cultural edicts of target subject populations would make research impossible under established CHS guidelines. Such exceptions must be well documented and will be considered on a case-by-case basis.