# Presentation: 013331

## Additional Safeguards for Vulnerable Subjects 

- September 29, 2005
- David Forster
- Western Institutional Review Board

## Vulnerable Subjects –Definition

- “Vulnerable” was not the best word choice for use in the 1981 NIH and FDA regulations
- Webster’s –
- 1. Capable of being physically wounded
- 2. Open to attack or damage

## Vulnerable Subjects –Historical Use of Term

- “The special considerations that should be given to children and infants are, first, that they are particularly vulnerable and helpless and therefore call for more consideration than other groups.”
- _Human Guinea Pigs_, M.H. Pappworth, 1967.

## Vulnerable Subjects –Historical Use of Concept

- Dr. Robert Marston, in a speech at University of Virginia on November 10, 1972, addressed the concept of individuals with “limited civil freedom,” and called for better protections for them.
- This included “prisoners, residents of institutions for the mentally retarded and mentally ill, and minors.”
- Hastings Center Report 3(2): 1-4, Apr 1973.

## Vulnerable Subjects –Historical Use of Term

- “Vulnerable” is not used in:
- The Nuremberg Code,
- The Declaration of Helsinki (until 2000 version),
- 1974 NIH regulations on subject protection, or
- The Belmont Report.
- Used in the 1981 NIH and FDA regulations.

## Vulnerable Subjects –The Belmont Report

-    The Belmont Report addressed the concept of vulnerability as part of the principle of Respect for Persons:
-   “Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.”

## Belmont Report quote

- “Not every human being is capable of self-determination. The capacity for self-determination matures during an individual’s life, and some individuals lose this capacity wholly or in part because of illness, mental disability, or circumstances that severely restrict liberty. Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated.”

## Elements of Autonomy

-     Capacity			Voluntariness
- 						Freedom from the
- 						control or influence 					of others.

## Vulnerable Subjects(Have Actual or Potential Limitations on Autonomy)

**Lack of Capacity**
- Children
- Mentally Disabled
- Temporary
- Fluctuating

**Limits on Voluntariness**
- (potential for control, coercion, undue influence, or manipulation)
-  Fatal or Incurable Disease
-  Emergency Situations
-  Hierarchical Social Structure
-  Economically Disadvantaged
-  Educationally Disadvantaged
-  Marginalized Social Groups

## Definitions

- Control - Physical restraints.
- Coercion - Use of a credible threat of harm or force to control another.
- Undue Influence - Misuse of a position of confidence or power to lead another to make a decision he would not otherwise have made.
- Manipulation - Deliberate management of conditions or information in such a way as to lead another to make a decision he would not otherwise have made.  Examples of information manipulation include lying, withholding information, and exaggeration.

## Constant Considerations about Vulnerability

- Within any population of vulnerable subjects, individuals will have different levels of vulnerability.
- The level of vulnerability of an individual may change due to changes in capacity or in conditions affecting voluntariness.
- The IRB considers a hypothetical group of subjects, whereas the investigator interacts with actual subjects.

## HHS Regulation 45 CFR 46.111(b) - Definition of Vulnerable Subjects

- “When some or all of the subjects, such as children, prisoners, pregnant women, handicapped or mentally disabled persons, or economically or educationally disadvantaged  persons, are likely to be vulnerable to coercion or undue influence [,] additional safeguards have been included in the study to protect the rights and welfare of these subjects.”

## ICH 1.61 - Definition of Vulnerable Subjects

- Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

## ICH 1.61 - Definition ofVulnerable Subjects (cont.)

- Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention.

## ICH 1.61 - Definition ofVulnerable Subjects (cont.)

- Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

## Children

- Wide range of capacity depending on age.
- Potential for control, coercion, undue influence, or manipulation by parents, guardians, or investigator.
- Are automatically vulnerable by regulation.

## Embryos and Fetuses

- Absolutely no capacity.
- Complete control by mother.
- Pregnant women and fetuses are automatically vulnerable by regulation.

## Mentally Disabled

- Problems with capacity, continuous or fluctuating.
- Often institutionalized or hospitalized.
- Often economically disadvantaged.
- Often educationally disadvantaged.
- Often have limited access to medical care.
- Potential for control, coercion, undue influence, or manipulation.
- Many suffer from incurable diseases.

## Emergency Situations

- Possible problems with capacity.
- Potential for control, coercion, undue influence, or manipulation.
- Limits on voluntariness due to time constraints.
- Institutional setting.

## Hierarchical Social Structure

- Potential for control, coercion, undue influence, or manipulation.
- Examples include: Prisoners, military personnel, employees, students, hospitalized patients, and residents of nursing homes and other medical institutions.
- Prisoners are automatically vulnerable by regulation.

## Educationally Disadvantaged

- May have limitations on understanding.
- May be illiterate.
- Potential for undue influence or manipulation.

## Economically Disadvantaged

- May enroll in research in order to receive treatment.
- May enroll in research solely for compensation (for example, Phase I drug studies).
- Often educationally disadvantaged in addition.
- Potential for undue influence or manipulation.

## Marginalized Social Groups

- Have little social power.
- Often not granted full access to social institutions, such as the legal system.
- Potential for control, coercion, undue influence, or manipulation.
- Many possible sources - disease, race, poverty, etc.

## Individuals with Fatal Disease

- May take very high risks in desperation for cure.
- Potential for undue influence or manipulation.
- May be problems with capacity, permanent or temporary, caused by disease or drugs.
- Vulnerability magnified in dying subjects.

## Individuals with Incurable Disease

- May take very high risks in desperation for cure.
- Potential for undue influence or manipulation.
- May be problems with capacity, permanent or temporary, caused by disease or drugs.

## What are additional safeguards for vulnerable subjects?

- Regulations – “When some or all of the subjects 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 subjects.” 46.111(b)

## What are additional safeguards for vulnerable subjects?

- The subpart A regulations do not provide a definition.
- However, subparts B, C, and D do provide examples.
- Congress tasked the National Commission with writing reports on research with pregnant women, prisoners, children, and the institutionalized mentally disabled.
- The first three reports are the basis for subparts B, C, and D of the NIH regulations (45 CFR 46).

## 21 CFR 50/45 CFR 46 - Subpart D

**§50.51/46.404 Clinical Investigations not involving greater than minimal risk.**
- 	Any clinical investigation . . . in which no greater than minimal risk to children is presented may involve children as subjects only if the IRB finds and documents that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians as set forth in §50.55/§46.408.

## 21 CFR 50/45 CFR 46 - Subpart D

**Additional Protections for Children Involved as Subjects in Research **
- Source: 48 FR 9818, March 8, 1983, unless otherwise noted.

## 21 CFR 50/45 CFR 46 - Subpart D

**§50.52 /46.404 Clinical investigations involving greater than minimal risk but presenting the prospect of direct benefit to individual subjects.**
- 	Any clinical investigation . . . in which more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, may involve children as subjects only if the IRB finds and documents that:

## 21 CFR 50/45 CFR 46 - Subpart D

- (a) the risk is justified by the anticipated benefit to the subjects;
- (b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches; and
- (c) adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians as set forth in 50.55.

## 21 CFR 50/45 CFR 46 - Subpart D

**§50.53/46.404 Clinical investigations 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.**
-  Any clinical investigation . . . in which 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 that is not likely to contribute to the well-being of the subject, may involve children as subjects only if the IRB finds and documents that:

## 21 CFR 50/45 CFR 46 - Subpart D

- (a) the risk represents a minor increase over minimal risk;
- (b) the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations;
- (c) the intervention or procedure is likely to yield generalizable knowledge about the subjects' disorder or condition which is of vital importance for the understanding or amelioration of the subjects' disorder or condition; and
- (d) adequate provisions are made for soliciting assent of the children and permission of their parents or guardians as set forth in 50.55/46.408.

## 21 CFR 50/45 CFR 46 - Subpart D

**§50.54/46.407 Clinical investigations not otherwise approvable that present an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.**
- 	If an IRB does not believe that a clinical investigation . . . involving children meets the requirements of §50.51, §50.52, or §50.53, the clinical investigation may proceed only if:
- (a) The IRB finds that the clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and

## 21 CFR 50/45 CFR 46 - Subpart D

- (b) The Commissioner of Food and Drugs, 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:
- that the research in fact satisfies the conditions of §50.51, §50.52, or §50.53, as applicable, or
- that the following conditions are met:

## 21 CFR 50/45 CFR 46 - Subpart D

- The clinical investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
- The clinical investigation will be conducted in accordance with sound ethical principles; and
- Adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians as set forth in 50.55.

## 21 CFR 50/45 CFR 46 - Subpart D

**50.55/46.408 Requirements for permission by parents or guardians and for assent by children.**

## 21 CFR 50/45 CFR 46 - Subpart D

- 50.56/46.409 Wards.
- (a) 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 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.

## 21 CFR 50/45 CFR 46 - Subpart D

- (b) If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis.

## 45 CFR 46 - Subpart B

**Additional Protections for Pregnant Women,                   Human Fetuses, and Neonates Involved in Research**
** ****(Revised November 13, 2001, FR 56775)**

## 45 CFR 46 - Subpart B

- Pregnant women or fetuses may be involved in research if all of the following conditions are met:
- (a) Where scientifically appropriate, preclinical 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;

## 45 CFR 46 - Subpart B

- (b) 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;

## 45 CFR 46 - Subpart B

- (h) No inducements, monetary or otherwise, will be offered to terminate a pregnancy;
- (i) 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
- (j) Individuals engaged in the research will have no part in determining the viability of a neonate.

## 45 CFR 46 - Subpart C

**Additional DHHS Protections **
**Pertaining to Biomedical and Behavioral Research**
**Involving Prisoners as Subjects**

## 45 CFR 46 - Subpart C

- §46.302 Purpose.
- Inasmuch as prisoners may be under constraints because of their incarceration which could affect their ability to make a truly voluntary and uncoerced decision whether or not to participate as subjects in research, it is the purpose of this subpart to provide additional safeguards for the protection of prisoners involved in activities to which this subpart is applicable.

## 45 CFR 46 - Subpart C

- §46.304 Composition of Institutional Review Boards where prisoners are involved.
- (a) A majority of the Board (exclusive of prisoner members) shall have no association with the prison(s) involved, apart from their membership on the Board.
- (b) At least one member of the Board shall be a prisoner, or a prisoner representative with appropriate background and experience to serve in that capacity.

## 45 CFR 46 - Subpart C

- §46.305 Additional duties of the Institutional Review Boards where prisoners are involved.
- (a) In addition to all other responsibilities prescribed for Institutional Review Boards under this part, the Board shall review research covered by this subpart and approve such research only if it finds that:
- (1) The research under review represents one of the categories of research permissible under §46.306(a)(2);

## 45 CFR 46 - Subpart C

- (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;

## 45 CFR 46 - Subpart C

- (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.

## Conclusion

- The use of additional safeguards provide extra protections for vulnerable subjects.
- They serve a paternalistic function, and administratively limit the choices open to subjects, investigators, IRBs, and agencies.
- in other words, they cut off some of the possible branches of choice in a decision-making tree.