Special Populations Supplement (Long)

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SPECIAL POPULATIONS SUPPLEMENT

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Instructions:  Complete this form if you wish to enroll members of a special population listed below in your research. The Institutional Review Board (IRB) needs to make specific, additional regulatory findings for inclusion of these special populations in research. o Wards/Foster Children o Neonates o Pregnant Women & Fetuses o Prisoners o Persons with Diminished Decision-Making Capacity/Mentally-Disabled Persons o Economically or Educationally Disadvantaged Persons o Note: Since children are so frequently participants of research at Seattle Children’s, the regulatory requirements for enrolling children have been incorporated into the main IRB-ITHS Application.  Please complete one or more of the applicable sections below, depending upon the populations to be included in your research.

Note: A consultation with a Human Subjects Protection Program (HSPP) analyst is recommended for any study involving any of the special populations contained in this supplement. Please see the IRB Web pages for more information about consultations.

Investigator Help: For more information, please see OHRP’s guidance on the topic of special populations.

Federal Regulations: When some or all of the participants are likely to be vulnerable to coercion or undue influence, such as children, prisoners, pregnant women, mentally-disabled persons, or economically or educationally disadvantaged persons, additional safeguards have been included in the study to protect the rights and welfare of these participants. 45 CFR 46.111(b).

1. Wards/Foster Children, 45 CFR 46.409

Federal Regulations: If wards are anticipated as research participants, the IRB must determine that they are appropriately included in the research. For studies where children who are wards of the state (or of any other agency, institution, or entity) are to be included in research approved under §46.406 or §46.407, special procedural requirements are dictated by the federal regulations. 45 CFR 46.409

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A ward is a child who is placed in the legal custody of the State or other agency, institution, or entity, consistent with applicable Federal, State, or local law. 21 CFR 50.3(q). This commonly includes foster children.

Research involving wards requires additional protections to ensure the safety and welfare of the wards are protected, including review and approval from the Washington State Department of Social and Health Services (DSHS). Seattle Children’s has entered into an Authorization Agreement with the Washington State DSHS to allow the DSHS to rely on Seattle Children’s IRB for review and continuing oversight of certain human subject(s) research involving foster children and/or wards of the state. There are two basic regulatory approaches to studies involving wards of the state:

 DSHS relies on Seattle Children’s IRB review: o If the research involves foster children or wards of the state for reasons unrelated to their status as foster children or wards of the state; and o The research is categorized by the Seattle Children’s IRB as 46.404 (minimal risk) or 46.405 (greater than minimal risk with prospect of direct benefit).  Dual review of the research by DSHS’ IRB and Seattle Children’s IRB: o If the research specifically targets foster children or wards of the state for reasons related to their status as foster children or wards of the state; or o The research is categorized by the Seattle Children’s IRB as 46.406 (greater than minimal risk and no prospect of direct benefit to individual participants, but likely to yield generalizable knowledge about the participants’ disorder or condition) or 46.407 (research not approval by a local IRB (requires review at the federal level)).

1.1. If you will enroll foster children/wards in the research, you must inform the IRB of the steps you will take to ensure that researchers will obtain legally effective informed consent.

Please explain the steps that will be followed here:

Investigator Help: This involves creating a plan for identifying the child’s legally authorized representative. According to the federal regulations, the term “guardian” means “an individual who is authorized under applicable State or local law to consent on behalf of a child to general medical care.” 45 CFR 46.402(e).

Seattle Children’s Policy : For local requirements, please see the Seattle Children’s policy, “Legally Authorized Person for Informed Consent Decision Making When a Patient is a Minor”, and the accompanying flow charts. It is advisable to make a note in the research record about the process that was followed to identify the legally authorized representative.

There are additional federal requirements for studies that are categorized by the IRB as 46.406 or 46.407, as described below (the requirements are not applicable if the research is category 46.404 or 46.405):

1.2. Under federal regulations, children who are wards of the state or any other agency, institution, or entity can be included in research approved under §46.406 or §46.407 in limited circumstances. Please indicate the type below (must check at least one): Related to their status as wards; or Conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as participants are not wards.

If the category 46.406 or 46.407 research is approved to enroll wards, the IRB shall require appointment of an advocate for each child who is a ward. This advocate is appointed 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.

2. Neonates, 45 CFR 46.205

The regulations define neonate as “a newborn,” and the IRB generally interprets this to mean a newborn up to 4 weeks of age.

Federal Regulations: The complete regulatory information relating to neonates can be found on the OHRP Web site.

2.1. Will all neonate participants be viable? Yes, all neonates will be viable.  You do not need to answer the remainder of the neonate questions because all viable neonates are treated as children under the regulations. Please answer the questions in the “Children” section of the main IRB-ITHS application and skip to section 3: Pregnant Women & Fetuses. No, neonates may not be viable.  Answer questions 2.1.1 - 2.1.11. below (and please contact a HSPP analyst with any questions).

Investigator Help: Viable, as it pertains to the neonate, means being able, after delivery, to survive (given the benefit of available medical therapy) to the point of independently maintaining heartbeat and respiration. 45 CFR 46.202(h). Guidelines published in the Federal Register in 1975 specify that an estimated gestational age of 20 weeks or more and a body weight of 500 grams or more are indices of fetal viability [Federal Register 40 (August 8, 1975): 33552].

Nonviable neonate means a neonate after delivery that, although living, is not viable. 45 CFR 46.202(e). Federal guidance suggests that “Although it may be presumed that an expelled or delivered fetus is nonviable at a gestational age less than 20 weeks and weight less than 500 grams [Federal Register 40 (August 8, 1975): 33552], a specific determination as to viability must be made by a physician in each instance.”

To include neonates of uncertain viability and/or nonviable neonates in the research, all of the criteria below must be satisfied. 45 CFR 46.205(a). Please provide an explanation for each item from the regulations, even if you just explain why the requirement is not

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2.1.1. Where scientifically appropriate, preclinical and clinical studies have been conducted and provide data for assessing potential risks to neonates.

2.1.2. Each individual providing consent is fully informed regarding the reasonably foreseeable impact of the research on the neonate.

2.1.3. Investigators and other individuals engaged in the research will have no part in determining the viability of a neonate.

For neonates of uncertain viability, until it has been ascertained whether or not a neonate is viable, a neonate may not be involved in the research unless additional conditions have been met. Please address these conditions below.

The IRB will need to determine that:

2.1.4. 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. OR

2.1.5. The purpose of the research is the development of important biomedical knowledge, which cannot be obtained by other means, and there will be no added risk to the neonate resulting from the research. AND

2.1.6. The legally effective informed consent of either parent of the neonate will be obtained or, if neither parent is able to consent because of unavailability, incompetence, or temporary incapacity, then the legally effective informed consent of either parent's legally authorized representative is obtained, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest.

A nonviable neonate may not be involved in research unless all of conditions below are met. Please address each required condition below.

2.1.7. Vital functions of the neonate will not be artificially maintained.

2.1.8. The research will not terminate the heartbeat or respiration of the neonate.

2.1.9. There will be no added risk to the neonate resulting from the research.

2.1.10.The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means. AND

2.1.11.The legally effective informed consent of both parents of the neonate is obtained, (note that the normal consent waiver and alteration provisions of §46.116(c) and (d) do not apply). If either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, then the informed consent of one parent of a nonviable neonate will suffice, 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 regulatory requirements here.

3. Pregnant Women & Fetuses, 45 CFR 46.204

Federal Regulations: The regulatory information provided below can be found on the OHRP Web site.

If you intend/anticipate that pregnant women or fetuses may be involved in this research, then ALL of the conditions below must be addressed. Please provide an explanation for each item, even if you just explain why the requirement is not applicable (note that sample answers are not provided because these issues are very specific to the particular study).

3.1. 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.

3.2. 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.

3.3. Any risk is the least possible for achieving the objectives of the research.

3.4. If the research holds out: a) the prospect of direct benefit to the pregnant woman; b) the prospect of direct benefit to both the pregnant woman and the fetus; or 3) no prospect of benefit for the woman or the fetus but the risk to the fetus is not greater than minimal and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means, then the consent of the pregnant woman is obtained in accordance with the normal informed consent provisions.

3.5. If the research holds out the prospect of direct benefit solely to the fetus, then the consent of the pregnant woman and the father of the fetus is obtained in accord with the normal informed consent provisions, 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.

3.6. Each individual providing consent under this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate.

3.7. For children who are pregnant, assent of the pregnant child and permission of the child’s parent/legally authorized representative are obtained in accordance with the federal regulations regarding protections for children involved in research.

3.8. No inducements, monetary or otherwise, will be offered to terminate a pregnancy.

3.9. 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

3.10. Individuals engaged in the research will have no part in determining the viability of a neonate.

4. Prisoners, 45 CFR 46.306

Federal Regulations: The regulatory information provided below can be found on the OHRP Web site.

Note: If you anticipate enrolling prisoners in the research, please contact a HSPP analyst for a consultation, as this population is not frequently enrolled at Seattle Children’s. If you did not anticipate enrolling prisoners but a subject becomes incarcerated after enrollment please notify the IRB immediately. IRB approval is required before further research activities with the incarcerated participant may occur.

A prisoner is any individual involuntarily confined or detained in a penal institution. The term is intended to encompass individuals sentenced to such an institution under a criminal or civil statute, individuals detained in other facilities by virtue of statutes or commitment procedures that provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. 45 CFR 46.406(c).

When prisoners are involved in the research, a different definition of “minimal risk” applies: the probability and magnitude of physical or psychological harm that is normally encountered in the daily lives, or in the routine medical, dental, or psychological examination of healthy persons. 45 CFR 46.303(d).

The IRB has additional regulatory duties when prisoners are involved in the research. Please provide information to assist the IRB with making the following additional findings.

4.1. Please describe any possible advantages accruing to the prisoner through his or her participation in the research.

4.2. Please speak to whether, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, these possible advantages are of such a magnitude that the prisoner’s ability to weigh the risks of the research against the value of such advantages in the limited choice environment of the prison could be impaired.

4.3. Are the risks involved in the research commensurate with risks that would be accepted by non-prisoner volunteers?

4.4. Are procedures for the selection of participants within the prison 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 participants must be selected randomly from the group of available prisoners who meet the characteristics needed for that particular research project).

4.5. Is the information presented in a language which is understandable to the research participant population?

4.6. Does adequate assurance exist that parole boards will not take into account a prisoner’s participation in the research in making decisions regarding parole, and is each prisoner clearly informed in advance that participation in the research will have no effect on his or her parole?

4.7. Could there be a need for follow-up examination or care of participants after the end of their participation? If so, have adequate provisions been made for such examination or care, taking into account the varying lengths of individual prisoners’ sentences, and for informing participants of this fact?

4.8. Biomedical or behavioral research conducted or supported by the DHHS may involve prisoners as participants only if:

 The institution responsible for the conduct of the research has certified to the Secretary that the IRB has approved the research under §46.305 of the DHHS regulations; and  The Secretary of DHHS determines that the proposed research involves only the types of research listed below.

Please indicate which types are applicable to the research (must select at least one): 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 participants. 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 participants. 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) provided that 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 his/her intent to approve such research. Research on practices, both innovative and accepted, which have the intent and reasonable probability of improving the health or well-being of the participant. In cases in 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.

5. Persons with Diminished Decision-Making Capacity/Mentally-Disabled Persons who may not be competent to provide informed consent or assent (e.g., cognitively impaired, critically ill, mental disorders, etc.)

Unlike research involving children, prisoners, etc., no additional DHHS regulations specifically govern research involving persons who are cognitively impaired. 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 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). The following definitions were excerpted from OHRP guidance:

 Cognitively Impaired: Having either a psychiatric disorder (e.g., psychosis, neurosis, personality or behavior disorders), an organic impairment (e.g., dementia) or a developmental disorder (e.g., mental retardation) that affects cognitive or emotional functions to the extent that capacity for judgment and reasoning is significantly diminished. Others, including persons 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, may also be compromised in their ability to make decisions in their best interests  Competence: Technically, a legal term, used to denote capacity to act on one's own behalf; the ability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. o Competence may fluctuate as a function of the natural course of a mental illness, response to treatment, effects of medication, general physical health, and other factors. Therefore, mental status should be re-evaluated periodically. As a designation of legal status, competence or incompetence pertains to an adjudication in court proceedings that a person's abilities are so diminished that his or her decisions or actions (e.g., writing a will) should have no legal effect. Such adjudications are often determined by inability to manage business or monetary affairs and do not necessarily reflect a person's ability to function in other situations.

 Incapacity: Refers to a person's mental status and means inability to understand information presented, to appreciate the consequences of acting (or not acting) on that information, and to make a choice. Often used as a synonym for incompetence.  Incompetence: Technically, a legal term meaning inability to manage one's own affairs. Often used as a synonym for incapacity.

As a general rule, 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 perfectly able to understand the matter of being a research participant, 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.

5.1. Please indicate the ages of the participants who may have diminished decision- making capacity/mental disability: Children (ages 0-17), who may be asked to assent to research participation. Adults (ages 18+), who may be asked to consent to research participation.

5.2. Please describe the procedures that will be used to evaluate the mental status of prospective participants to determine whether they are capable of consenting/assenting to the research. The IRB will consider whether the procedures are appropriate to the participant population and the nature of the proposed research.

5.3. If participants are judged to be incapable of providing valid consent/assent for the research, will you be able to determine whether the participant objects to participation? Please describe.

5.4. For children who are not competent, the parent is able to provide permission for their participation in most cases, per the usual assent process.

For adults who are not competent, please see the related Seattle Children’s policy provided below.

Please explain the process that will be followed if adult patients are not competent to consent to participation:

Investigator Help: It is advisable to make a note in the research record about the process that was followed to identify the legally authorized representative.

For additional information on this topic, please see the National Institutes of Health guidance.

Seattle Children’s Policy: Please see the sections on developmentally-disabled individuals and incapacitated individuals with court-appointed guardians in the Seattle Children’s policy, “Legally Authorized Person for Informed Consent Decision Making When a Patient is a Minor”, and the accompanying flow charts. It is advisable to make a note in

the research record about the process that was followed to identify the legally authorized representative.

6. Economically or Educationally-Disadvantaged Persons

6.1. Please describe the nature of the economic or educational disadvantage that may be present in the participant population.

6.2. What steps will you take to minimize the effect of this disadvantage?

Investigator Help: For example, you might explain why the amount of the incentive offered will not unduly influence potential participants. For educational disadvantage, you might say that the reading level will be well below the 8th grade level, etc.

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