10. Vulnerable Populations

10 Vulnerable Populations

10.1 Research Involving Children

10.1.1 Federal Definitions under 45 CFR 46

10.1.2 Massachusetts Law

10.1.3 Allowable Categories

10.1.4 Parental Permission and Assent

10.1.4.1 Parental Permission

10.1.4.2 Assent from Children

10.1.4.3 Children Who are Wards

10.2 Research Involving Pregnant Women, Human Fetuses and Neonates

10.2.1 Definitions

10.2.2 Research Involving Pregnant Women or Fetuses

10.2.3 Research involving neonates

10.2.4 Research Involving, After Delivery, the Placenta, the Dead Fetus or Fetal Material

10.2.5 Research Not Otherwise Approvable

10.3 Research Involving Prisoners

10.3.1 Applicability

10.3.2 Purpose

10.3.3 Definitions

10.3.4 Composition of the CUHS

10.3.5 Additional Duties of the CUHS

10.3.6 Waiver for Epidemiology Research

10.3.7 Expedited Review and Exempt Research

10.4 Persons with Mental Disabilities or Persons with Impaired Decision-Making Capacity

10.4.1 CUHS composition

10.4.2 Approval Criteria

10.4.3 Additional Concerns

10.5 Subjects with Economic or Educational Disadvantages

10 Vulnerable Populations 

10.1 Research Involving Children 

Research involving children is governed by 45 CFR 46, Subpart D. 

10.1.1 Federal Definitions under 45 CFR 46 

Children - persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the research will be conducted. 

Assent - a child's affirmative agreement to participate in research. Mere failure to object, absent affirmative agreement, should not be construed as assent. 

Permission - the agreement of parent(s) or legal guardian to the participation of their child or ward in research. 

Parent - a child's biological or adoptive parent. 

Guardian - an individual who is authorized under applicable state or local law to consent on behalf of a child to general medical care. 

10.1.2 Massachusetts Law 

Age of majority. Eighteen is the age of majority both in Massachusetts (M.G.L. c. 231, § 85P) and under federal policy. When a person turns 18, s/he is considered to be an adult under the law. 

Massachusetts law recognizes two instances when teenagers under the age of 18 may have the legal capacity to consent to medical treatment. These are the emancipated minor and mature minor rules. Note that these rules concern individuals in their capacity as patients, not as subjects in research, and also that they apply only to persons in Massachusetts. These rules would not apply, for example, to research subjects living in a foreign country, although that country might have analogous rules 

Emancipated minor. A patient under 18 years of age may consent to treatment of any kind, except abortion, and may authorize the release of his or her medical records if he or she is: (a) married/widowed/divorced, a parent, (b) a member of the armed forces, (c) living apart from parents and managing his or her own finances, or, in the case of a female, (d) pregnant or believes herself to be pregnant. M.G.L. c. 112 § 12F. A female under the age of 18 may consent to an abortion if she is or has been married. Otherwise, consent must be obtained from her parent(s) or the procedure must be authorized by court order. M.G.L. c. 112 § 12S. Further, patients under 18 years of age may consent to treatment and may authorize the release of their medical records relating to: diseases dangerous to the public health, drug dependency (but not alcohol dependency), and pregnancy (but not abortion, except in the case of those who had married). 

Mature minor. Under Massachusetts case law, students under the age of 18 who are not emancipated under M.G.L. c. 112, § 12F, can, in certain circumstances, nevertheless consent to treatment and control access to their medical records. In such cases, the clinician proposing to provide the treatment may determine that the patient is a mature minor capable of consenting to treatment. To reach this determination, the clinician must conclude that the minor is capable of giving informed consent to the treatment; and that it is in the best interest of the minor not to notify his or her parents of the intended medical treatment. In general, where a minor has the capacity to consent to medical treatment, that minor also has the capacity to control his or her medical records, including releasing them to others, such as researchers. In addition, there is an argument that a minor who has the capacity to consent to medical treatment also should have the capacity to consent to research that may accompany that treatment. However, this argument has not been tested in a Massachusetts court. 

Parents or Guardians of minor children. In general, and as more fully explained below, parents and guardians may provide consent to participation in research for their children or wards. The definition of who is a parent or guardian differs in some respects under federal and Massachusetts laws. The Massachusetts Uniform Statutory Will Act (the “Will Act”) indirectly defines “parent” in its definition of “child.” See M.G.L. c. 191B, § 1(1). Under this law, the “parent” is the biological or adoptive mother or father of a child. However, a father of a child who is not married to the child’s mother may not always be considered a parent; his status would depend on whether he openly treats the child as his offspring or on whether a court has made a paternity determination. Under the Will Act, the term “parent” does not include step-parents who have not formally adopted the child, foster parents, grandparents or other relatives. Id. In general, the term “guardian” is widely understood to mean a person lawfully invested with the power, and charged with the duty, of taking care of and managing the property and rights of someone who is considered incapable of administering his or her own affairs. This definition includes a person who legally has responsibility for the care and management of the person or estate or both of a child during his or her minority. Parents are usually considered the guardians of their children under Massachusetts law. For example, with respect to children, the Department of Mental Retardation defines “guardian” in its regulations concerning research as “a natural or adoptive parent, or the individual or agency with legal guardianship of the person.” 115 CMR 10.02. In order for a non-parent to grant permission for a child to take part in research, the person has to meet the definition of “guardian” as defined by DHHS regulations; individuals who meet the “widely understood term guardian” cannot grant permission for a child to take part in research, unless the person also meets the definition of “guardian” as defined by DHHS regulations. 

Legal guardianship in Massachusetts usually is created through a court process, most often through the Probate Court, M.G.L. c. 201 § 2, although parents may designate another adult to be a guardian without having to invoke a court proceeding. This kind of guardian, once appointed, is also referred to as a “standby proxy,” whose authority becomes enforceable when the parent dies, becomes incapacitated or is unavailable to care for the child. M.G.L. c. 201 §§ 2B – 2D. The Department of Social Services or other state agencies may become the legal guardian of children it takes into custody. Legal guardians acting with authority pursuant to M.G.L. c. 201 §§ 2, 2B – 2D may consent on behalf of a child to general medical care, and so meet the DHHS definition of “guardian.” 

In general, a parent or legal guardian is considered under federal policy to be the Legally Authorized Representative (“LAR”) of a child, and thus may consent to the child’s participation in a research project. Thus, for a child subject in research, a parent or guardian acting as an LAR can give permission (consent) on behalf of the child to participate in research. As discussed above, an exception to this general rule is where the research involves medical treatment and the child has the capacity to consent under the emancipated minor or mature minor rules. 

When research that involves children is to be conducted outside Massachusetts, the CUHS will consult with the Office of General Counsel when any issue arises regarding the applicable law of the jurisdiction for establishing who are “children” and “guardians”, see 45 CFR §46.402 (a), (e). 

10.1.3 Allowable Categories 

Research on children must be reviewed and categorized by the CUHS into one of the following groups: 

1. Research not involving physical or emotional risk greater than that ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests (i.e., minimal risk). [45 CFR 46.404] 

• The CUHS must find that adequate provisions are made for the permission of their parents or guardians, as set forth in 45 CFR §46.408. 

• The CUHS must find that adequate provisions are made for soliciting the assent of the children, as set forth in 45 CFR §46.408. 

• The permission of both parents is required if both parents are alive, known, competent, reasonably available, and have legal responsibility for the care and custody of the child. Otherwise the permission of one parent is required. 

• The CUHS may determine that the permission of one parent is sufficient, even if the other parent is alive, known, competent, reasonably available, and shares legal responsibility for the care and custody of the child. 

2. Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subject. [45 CFR 46.405] 

• The risk is justified by the anticipated benefit to the subjects; 

• The CUHS must find that adequate provisions are made for the permission of their parents or guardians, as set forth in 45 CFR §46.408 

• The CUHS must find that adequate provisions are made for soliciting the assent of the children, as set forth in 45 CFR §46.408. 

• The permission of both parents is required if both parents are alive, known, competent, reasonably available, and have legal responsibility for the care and custody of the child. Otherwise the permission of one parent is required. 

• The CUHS may determine that the permission of one parent is sufficient, even if the other parent is alive, known, competent, reasonably available, and shares legal responsibility for the care and custody of the child. 

3. Research involving greater than minimal risk and no reasonable prospect of direct benefit to the individual subject, but likely to yield generalizable knowledge about the subject's disorder or condition. [45 CFR 46.406] 

• The risk represents a minor increase over minimal risk; 

• 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; 

• The CUHS must find that adequate provisions are made for the permission of their parents or guardians, as set forth in 45 CFR §46.408. 

• The CUHS must find that adequate provisions are made for soliciting the assent of the children, as set forth in 45 CFR §46.408. 

• The permission of both parents is required if both parents are alive, known, competent, reasonably available, and have legal responsibility for the care and custody of the child. Otherwise the permission of one parent is required. 

4. Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate serious problems affecting the health or welfare of children. [45 CFR 46.407] 

• Research in this category must be approved by the Secretary of the Department of Health and Human Services, and requires consent of both parents, or legal guardian (unless one parent is deceased, unknown, incompetent, or not reasonably available, or only one parent has legal responsibility for the care and custody of the child). 

• The CUHS must find that adequate provisions are made for the permission of their parents or guardians, as set forth in 45 CFR §46.408. 

• The CUHS must find that adequate provisions are made for soliciting the assent of the children, as set forth in 45 CFR §46.408. 

• The permission of both parents is required if both parents are alive, known, competent, reasonably available, and have legal responsibility for the care and custody of the child. Otherwise the permission of one parent is required 

10.1.4 Parental Permission and Assent 

10.1.4.1 Parental Permission 

In accordance with 45 CFR 46.408(b) the CUHS must determine that adequate provisions have been made for soliciting the permission of each child’s parent or guardian. 

Parents or guardians must be provided with the basic elements of consent as stated in 45 CFR 46.116(a)(1-8) and any additional elements the CUHS deems necessary. 

The CUHS may find that the permission of one parent is sufficient for research to be conducted under 45 CFR 46.404 or 45 CFR 46.405. Determination of whether consent must be obtained from one or both parents will be documented in the consent checklist when a protocol receives expedited review, and in meeting minutes when reviewed by the convened committee. 

Consent from both parents is required for research to be conducted under 45 CFR 46.404, 45CFR 46.405, 45 CFR 46.406 and 45 CFR 46.407 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 CUHS may waive the requirement for obtaining consent from a parent or legal guardian if: 

• The research meets the provisions for waiver in 45 CFR 46.116(d)(1-4) and if the CUHS determines that the research protocol is designed for conditions or a subject population for which parental or guardian permission is not a reasonable requirements to protect the subjects (for example, neglected or abused children). 

• An appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and 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. 

Permission from parents or legal guardians must be documented in accordance with and to the extent required by 45 CFR 46.117. 

10.1.4.2 Assent from Children 

Because “assent” means a child’s affirmative agreement to participate in research, (45 CFR 46.402(b)), the child must actively show his or her willingness to participate in the research, rather than just complying with directions to participate and not resisting in any way. When judging whether children are capable of assent, the CUHS must 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 CUHS deems appropriate. 

When reviewing the proposed assent procedure and the form and content of the information conveyed to the prospective subjects, the CUHS again takes into account the ages, maturity, and psychological state of the children involved as well as the nature of the proposed research activity. For research activities involving adolescents whose capacity to understand approaches that of adults, the assent procedure should likewise include information similar to what would be provided for informed consent by adults or for parental permission. For children whose age and maturity level limits their ability to fully comprehend the nature of the research activity, but who are still capable of being consulted about participation in research, it may be appropriate to focus on conveying an accurate picture of what the actual experience of participation in research is likely to be (for example, what will happen, how long it will take, whether it might involve any pain or discomfort). The assent procedure should reflect a reasonable effort to enable the child to understand, to the degree he or she is capable, what participation in research would involve. 

If the CUHS 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 (e.g., new therapy when no other option is available), then the assent of the children is not a necessary condition for proceeding with the research. In addition, even where the CUHS determines that the minor subjects are capable of assenting, it still may waive the assent requirement in accord with 45 CFR § 46.116. 

For children ages 7 and under, the CUHS recommends that the researchers verbally explain the study to the child, including its purpose, procedures, and potential risks and benefits (if appropriate, depending on the child’s age, maturity and development). Generally, oral assent through the use of a script should be obtained from children ages 7 through 11 years of age. The CUHS may require written assent from older children. For children ages 11 and under in particular, investigators should consider obtaining assent in the presence of a parent or legal guardian, unless the study procedures are taking place in a setting (such as a school) where parents are not usually present. 

Massachusetts regulations forbid the use of children in research involving controlled substances where the child has refused to consent to the research. 105 CMR §700.009(E) (4). 

The Assent Form 

When written assent is recommended, researchers should try to draft a form that is age appropriate and study specific, taking into account the typical child's experience and level of understanding, and composing a document that treats 

the child respectfully and conveys the essential information about the study. The assent form should: 

1. tell why the research is being conducted; 

2. describe what will happen and for how long or how often; 

3. say that it's up to the child to participate and that it's okay to say no; 

4. explain whether it will hurt and, if so, for how long and how often; 

5. say what the child's other choices are; 

6. describe any good things that might happen; 

7. say whether there is any compensation for participating; and 

8. ask for questions. 

For younger children, the document should be limited to one page if possible. Illustrations may be helpful, and larger type makes a form easier for young children to read. Studies involving older children or adolescents should include more information and may use more complex language. 

10.1.4.3 Children Who are Wards 

Under 45 CFR § 46.409(a), children who are wards of the state or any other agency, institution, or entity can be included in 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, only if such research is: 

1. related to their status as wards; or 

2. conducted in schools, camps, hospitals, institutions, or similar settings in which the majority of children involved as subjects are not wards. 

Even if the research meets the condition(s) above, 45 CFR § 46.409(b) requires that an advocate must be appointed for each child who is a ward (one individual may serve as advocate for more than one child), in addition to any other individual acting on behalf of the child as legal guardian or in loco parentis. 

The advocate must 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 CUHS) with the research, the investigator(s), or the guardian organization. 

Massachusetts law (M.G.L. Chapter 119, et. seq.) allows the Department of Social Services (“DSS”) to remove children from their parents’ custody in certain circumstances, but the placement of a child in foster care does not automatically terminate all parental rights. Because these situations are complicated, 

investigators who wish to use foster children as subjects in their research are urged to consult in advance with the CUHS. 

10.2 Research Involving Pregnant Women, Human Fetuses and Neonates 

10.2.1 Definitions 

Dead fetus - a fetus that exhibits neither heartbeat, spontaneous respiratory activity, spontaneous movement of voluntary muscles, nor pulsation of the umbilical cord. 

Delivery - complete separation of the fetus from the woman by expulsion or extraction or any other means. 

Fetus - the product of conception from implantation until delivery. 

Neonate - a newborn. 

Nonviable neonate - a neonate after delivery that, although living, is not viable. 

Pregnancy encompasses the period of time from implantation until delivery. A woman is assumed to be pregnant if she exhibits any of the pertinent presumptive signs of pregnancy, such as missed menses, until the results of a pregnancy test are negative or until delivery. 

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. 

10.2.2 Research Involving Pregnant Women or Fetuses 

Under 45 CFR § 46.204, pregnant women or fetuses may be involved in research if all of the following conditions are met: 

1. Where scientifically appropriate, pre-clinical studies, including studies on pregnant animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses; 

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

4. If the research holds out the prospect of direct benefit to the pregnant woman, the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman nor the fetus when 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, her consent is obtained in accord with the provisions for informed consent; 

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 is obtained in accord with the provisions for informed consent, 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. 

6. Each individual providing consent under paragraph 4. or 5. of this section is fully informed regarding the reasonably foreseeable impact of the research on the fetus or neonate; 

7. For children who are pregnant, assent and permission are obtained in accord with the provisions of permission and assent; 

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

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 

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

Experimentation on human fetuses is also regulated under Massachusetts law, M.G.L. Chapter 112C, § 12J(a), which states in part: 

I. No person shall use any live human fetus whether before or after expulsion from its mother’s womb, for scientific, laboratory, research or other kind of experimentation. This section shall not prohibit procedures incident to the study of a human fetus while it is in its mother’s womb, provided that in the best medical judgment of the physician, made at the time of the study, said procedures do not substantially jeopardize the life or health of the fetus, and provided said fetus is not the subject of a planned abortion. . . . This section shall not prohibit or regulate diagnostic or remedial procedures the purpose of which is to determine the life or health of the fetus involved or to preserve the life or health of the fetus involved or the mother involved. . . . 

II. No experimentation may knowingly be performed upon a dead fetus unless the consent of the mother has first been obtained, provided, however, that such consent shall not be required in the case of a routine pathological study. . . . 

III. No person shall perform or offer to perform an abortion where part or all of the consideration for said performance is that the fetal remains may be used for experimentation or other kind of research or study. 

IV. No person shall knowingly sell, transfer, distribute or give away any fetus for a use which is in violation of the provisions of this section. . . . 

The Massachusetts statute includes criminal penalties, but states that those who have performed a procedure that allegedly violates the statute’s provisions will not be held liable if: (i) the procedure received the written approval of a duly appointed IRB; and (ii) at the time the procedure was performed, there was not an outstanding court judgment that the procedure violated the statute. The IRB’s written approval must state specifically that the procedure does not violate the provisions of the statute and must set forth a reasonable basis for this conclusion. M.G.L. Chapter 112C, § 12J(a)(V-VII). IRB members are themselves immune from liability under the statute if they acted in good faith in concluding that the procedure was lawful. M.G.L. Chapter 112C, § 12J(a)(VI). 

10.2.3 Research involving neonates 

[45 CFR 46.205] 

Neonates of uncertain viability and nonviable neonates may be involved in research if all of the following conditions are met: 

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

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

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

4. The requirements of Neonates of Uncertain Viability or Nonviable Neonates (see below in this section) have been met as applicable. 

Neonates of Uncertain Viability. 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 following additional conditions have been met: 

The CUHS determines that: 

1. 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. 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 

3. 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 the provisions of permission and assent, except that the consent of the father or his legally authorized representative need not be obtained if the pregnancy resulted from rape or incest. 

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

1. Vital functions of the neonate will not be artificially maintained; 

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

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

4. The purpose of the research is the development of important biomedical knowledge that cannot be obtained by other means; and 

5. The legally effective informed consent of both parents of the neonate is obtained in accord with the provisions of permission and assent, except that the waiver and alteration of the provisions of permission and assent do not apply. 

6. However, if either parent is unable to consent because of unavailability, incompetence, or temporary incapacity, the informed consent of one parent of a nonviable neonate will suffice to meet the requirements of this paragraph, 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. 

Viable Neonates. 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 CUHS Review Process for Research Involving Children [see section 10.1]. 

10.2.4 Research Involving, After Delivery, the Placenta, the Dead Fetus or Fetal Material 

[45 CFR 46.206] 

1. Research involving, after delivery, the placenta; the dead fetus; macerated fetal material; or cells, tissue, or organs excised from a dead fetus, must be conducted only in accord with any applicable Federal, State, or local laws and regulations regarding such activities. 

2. If information associated with material described above in this section is recorded for research purposes in a manner that living individuals can be 

identified, directly or through identifiers linked to those individuals, those individuals are research subjects and all pertinent sections of this manual are applicable. 

10.2.5 Research Not Otherwise Approvable 

[45 CFR 46.207] 

The Secretary of the Department of Health and Human Services (DHHS) will fund research that the CUHS does not believe meets the requirements of Research Involving Pregnant Women or Fetuses or Research Involving Neonates only if: 

1. The CUHS 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 pregnant women, fetuses or neonates; and 

2. The Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, ethics, law) and following opportunity for public review and comment, including a public meeting announced in the Federal Register, has determined either: 

a. That the research in fact satisfies the conditions of Research Involving Pregnant Women or Fetuses, as applicable; 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 pregnant women, fetuses or neonates; 

2) The research will be conducted in accord with sound ethical principles; and 

3) Informed consent will be obtained in accord with the provisions for informed consent and other applicable sections of this manual. 

10.3 Research Involving Prisoners 

Research involving prisoners is governed by 45 CFR 46, Subpart C, as applicable. 

10.3.1 Applicability 

This policy applies to all research conducted under the auspices of the University-Area institutions involving prisoners as subjects. Even though the CUHS may approve a research protocol involving prisoners as subjects according to this policy, investigators are still subject to the Administrative 

Regulations of the Massachusetts Department of Corrections and any other applicable state or local law. [45 CFR 46.301] 

10.3.2 Purpose 

The incarceration of prisoners may affect their ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in research. In consequence, additional safeguards are appropriate for the protection of prisoners involved in research activities. [see 45 CFR 46.302] 

10.3.3 Definitions 

[45 CFR 46.303] 

Prisoner – 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 which provide alternatives to criminal prosecution or incarceration in a penal institution, and individuals detained pending arraignment, trial, or sentencing. The CUHS interprets this definition to include individuals who are sent by court order to alcohol/drug rehabilitation facilities. 

These additional protections apply not just to individuals who are prisoners at the time they are enrolled in a study, but also to those who become incarcerated during the course of a study

Minimal Risk – 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. 

10.3.4 Composition of the CUHS 

[45 CFR 46.304] 

In addition to satisfying the general requirements detailed in the CUHS section of this manual, when reviewing research involving prisoners, the CUHS must also meet the following requirements: 

1. A majority of the CUHS (exclusive of prisoner members) must have no association with the prison(s) involved, apart from their membership on the CUHS. 

2. At least one member of the CUHS must be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity, except that where a particular research project is reviewed by more than one IRB, only one IRB need satisfy this requirement. 

10.3.5 Additional Duties of the CUHS 

[45 CFR 46.305] 

In addition to all other responsibilities prescribed for the CUHS in the CUHS Institutional Review Board and CUHS Review Process sections of this manual, the CUHS will review research involving prisoners and approve such research only if it finds that: 

1. the research falls into one of the following permitted categories [45 CFR 46.306]: 

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. 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, research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) provided that any study conducted or supported by DHHS may proceed only after certification to the Secretary, 45 CFR 46.305(c), and the Secretary of DHHS has consulted with appropriate experts including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the Secretary’s intent to approve such research; 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. 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, any study conducted or supported by DHHS may proceed only after certification to the Secretary, 45 CFR 46.305(c), and the Secretary of DHHS has consulted with appropriate experts, including experts in penology, medicine, and ethics, and published notice, in the Federal Register, of the Secretary’s intent to approve such research. 

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 non-prisoner 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 CUHS 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 CUHS finds there may be a need for follow-up examination or care of subjects 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 subjects of this fact. 

For research conducted or supported by DHHS, the institution responsible for the conduct of the research shall certify to the Secretary that the CUHS has fulfilled its duties under 45 CFR 46 Subpart C; the Secretary of the DHHS may assign further duties to the CUHS. 45 CFR §§ 46.305(b)-(c). 

10.3.6 Waiver for Epidemiology Research 

The Secretary of DHHS has waived the applicability of 45 CFR 46.305(a)(l) and 46.306(a)(2) for certain research conducted or supported by DHHS that involves epidemiologic studies and that meet the following criteria: 

(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 IRB has 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. 

The specific type of epidemiological research subject to the waiver involves no more than minimal risk and no more than inconvenience to the human subject 

participants. The waiver would allow the conduct of minimal risk research that does not now fall within the categories set out in 45 CFR 46.306(a)(2). 

The range of studies to which the waiver would apply includes epidemiological research related to chronic diseases, injuries, and environmental health. This type of research uses epidemiologic methods (such as interviews and collection of biologic specimens) that generally entail no more than minimal risk to the subjects. 

In order for a study to be approved under this waiver, the CUHS would need to ensure that, among other things, there are adequate provisions to protect the privacy of subjects and to maintain the confidentiality of the data. 

10.3.7 Expedited Review and Exempt Research 

Ordinarily, the CUHS will not expedite its review of research involving prisoners, although expedited review procedures are permitted under 45 CFR § 46.110 and 21 CFR § 56.110 for minor changes in approved research and for certain kinds of research involving no more than minimal risk. As noted above, with respect to research involving prisoners, the CUHS applies the definition of “minimal risk” set forth in 45 CFR § 46.303(d). 

The exemptions set forth in 45 CFR § 46.101(b) do not apply to research involving prisoners. 45 CFR § 46.101(i), FN1. 

10.4 Persons with Mental Disabilities or Persons with Impaired Decision-Making Capacity 

Ordinarily, an investigator must obtain informed consent directly from prospective research subjects. When the prospective research subject is an adult whose own consent would not be legally effective because s/he lacks the capacity to give or communicate comprehending, informed consent, then research may be conducted only with the consent of the potential subject’s legally authorized representative (the “LAR”), which is also known as “surrogate consent.” This policy is designed to protect human subjects from exploitation and harm and, at the same time, make it possible to conduct research on problems that are unique to persons who are incompetent, or who have an impaired decision-making capacity. 

The federal regulations define “legally authorized representative” as “an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research.”5 Under Massachusetts law, this means the consent must come either from the legal guardian of the subject, or, in the case of research that is part of medical treatment, from the subject’s health care agent 

(either as appointed under the Massachusetts health care proxy law, or as designated by a health care provider under the common law for obtaining consent to the provision of medical care and associated procedures). If the subject is able to give assent (affirmative agreement) as well, this is required but the CUHS may waive the requirement to seek assent if the subject is not competent to give it. 

The Massachusetts Department of Mental Retardation regulations concerning research are useful in understanding how Massachusetts defines “guardian.” Those regulations state that “with respect to persons 18 years of age and older,” a guardian is the “individual, organization or agency, if any, that has been appointed legal guardian of the person found to be incompetent by a court of competent jurisdiction.”6 115 CMR 10.02. Massachusetts law allows for guardianships to be created for persons who are judged to be mentally ill or mentally retarded, or for persons judged unable to communicate informed decisions. M.G.L. c. 201 §§ 6, 6A, 6B. The guardianship law does not enumerate all of the guardian’s authority, except to say that the guardian “shall have the care and custody of his ward . . . and the management of all his estate.” As this authority is generally accepted to mean that the guardian may take all actions for the ward that the ward might have taken if competent, there is no reason to believe that the ability to consent to research is not within the guardian’s authority. Indeed, this view is consistent with the manner in which the Department of Mental Retardation conducts its research using consent from guardians. See 115 CMR 10.00. 

Massachusetts law provides for proxy consent for medical decisions to be given on behalf of a patient who lacks the capacity to consent. The law allows a competent adult to appoint a designated person as his or her “health care agent.”7 If the person then becomes incapacitated, and is in need of medical care, the health care proxy becomes empowered to make medical decisions on his or her behalf. If no health care agent has been appointed in advance, then medical care providers are authorized by the law to accept consent from “responsible parties,” under common law principles, usually meaning the patient’s next-of-kin.8 It is generally accepted in Massachusetts that if research involves the provision of medical care, a health care agent, whether appointed or holding that status by virtue of being a “responsible party,” may consent to that treatment and to the accompanying research. 

In light of Massachusetts law, federal policy, and existing judicial opinions on the interrelationships of the two, it is unclear whether an IRB may approve a study that involves consent by an LAR for a cognitively-impaired adult to participate in non-medical research in the Commonwealth with more than minimal risk. In 

such situations, before approving consent by an LAR, the CUHS must attend closely to the ethical considerations discussed in the Belmont Report (respect for persons (autonomy of subjects), beneficence, and justice) as well as the possible interpretations of existing law. The CUHS reasonably may look for guidance to closely similar situations in which the Belmont Report principles were applied, in determining appropriate consent/permission/assent processes for research under its review. A reasonable solution that balances interests frequently is possible following appropriate discussion and consideration by the CUHS. The Office of General Counsel will be consulted for each study involving adults unable to consent in Massachusetts for a determination of which individuals are legally authorized representatives under Massachusetts law to consent on behalf of subjects to their participation in the procedures involved in the research. For studies that involve adults unable to consent that will be conducted outside Massachusetts, the Office of General Counsel will be consulted regarding the applicable law of the jurisdiction for establishing who is an LAR, see 45 CFR § 46.102(c). However, it is possible that a study may be approved by the CUHS, but may not be permitted to proceed by the University (under advice of counsel or otherwise). 

The CUHS may require investigators to conduct a preliminary competency assessment whenever there is a possibility of either impaired mental status or decision-making capacity in prospective subjects. 

If feasible, the investigator must explain the proposed research to the prospective research subject even when a surrogate gives consent. Under no circumstances may a subject be forced or coerced to participate in a research study. 

Under 104 C.M.R. § 31.00, et. seq., the Massachusetts Department of Mental Health has the jurisdiction to review and approve any human research “related to” the Department, its facilities or programs in which its “clients” are proposed subjects. Researchers whose proposals fall within the DMH’s jurisdiction must submit them to a DMH IRB for approval. In such cases, the CUHS ordinarily will designate the DMH IRB as the IRB of record and will enter into an IRB authorization agreement with DMH. However, in all such situations the CUHS independently will consider the study population, paying particular attention to the potential subjects’ ability to provide informed consent. 

10.4.1 CUHS composition 

The CUHS membership must include at least one member who has appropriate background and experience concerning individuals with mental disabilities or impaired decision-making capacity. Consideration may be given to adding another member who is a member of the population, a family member of such a person or a representative of an advocacy group for that population, or to consulting with such a person as appropriate. 

10.4.2 Approval Criteria 

Research involving persons with impaired decision-making capability may only be approved when the following conditions apply: 

1. The investigator demonstrates to the CUHS that there is a compelling reason to include incompetent individuals or persons with impaired decision-making capacity as subjects. Incompetent persons or persons with impaired decision-making capacity must not be subjects in research simply because they are readily available. 

2. The proposed research entails no significant risks, tangible or intangible, or if the research presents some probability of harm, there must be at least a greater probability of direct benefit to the subject. Incompetent people or persons with impaired decision-making capacity are not to be subjects of research that imposes a risk of injury, unless that research is intended to benefit that subject and the probability of benefit is greater than the probability of harm. 

3. Procedures have been devised to ensure that participant’s representatives are well informed regarding their roles and obligations to protect incompetent subjects or persons with impaired decision making capacity. Health care agents [appointed under the Massachusetts health care proxy law] or guardians must be given descriptions of both the proposed research study and the obligations of the person’s representative(s). They must be told that their obligation is to try to determine what the subject would do if competent, or if the subject's wishes cannot be determined, what they think is in the incompetent person's best interest. 

10.4.3 Additional Concerns 

Both investigators and CUHS members must be aware that some subjects’ decision-making capacity may fluctuate. For subjects with fluctuating decision making capacity or those with decreasing capacity to give consent, a re-consenting process with surrogate consent may be necessary. It is the responsibility of investigators to monitor the decision-making capacity of subjects enrolled in research studies and to determine if it is appropriate to request that a surrogate reaffirm consent after consideration of all consent issues. 

10.5 Subjects with Economic or Educational Disadvantages 

Investigators at times perform research, both in the United States and abroad, with people who have limited resources in terms of finances, goods, and/or access to health care and other services. The CUHS pays particular attention to remuneration and other inducements that might encourage people with limited resources to participate in research projects in which they might not otherwise participate. Compensation should not be the sole grounds for participation in a research project, and should not cause participants to assume risks that they would not ordinarily find acceptable. 

The CUHS considers persons with limited resources to be vulnerable to the extent that inducements to participate in research may result in their acting against their own best interests. Where the population from which subjects will be recruited primarily consists of people with limited resources, the CUHS will look carefully at recruitment procedures, the potential risks in relation to the compensation being offered, and the potential benefits irrespective of compensation. The investigator will be asked to justify the compensation being offered. If the CUHS finds it to be coercive, then the CUHS will ask the investigator to provide alternative compensation so as not to impede the subjects’ decision about whether they should participate in the research project.