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Special Classes of Subjects — Vulnerable Subjects

Currently, PNNL does not conduct research involving vulnerable subjects. The IRB has not, therefore, established formal policies and procedures to conduct or review research involving these subjects as defined under federal regulation, 45 CFR 46, Subparts B, C, and D.

Investigators who need to use pregnant women, fetuses, children, or prisoners or any other vulnerable population in their research should contact the IRB as early as possible to ensure that current policies and procedures are properly established to conduct and review this research. The following information is provided as guidance for IRB members and for investigators who might be considering future use of vulnerable subjects in their research.

There are a number of research populations described in the federal regulations as "vulnerable" or that require additional consideration or protection. "Vulnerable" or special classes of subjects include, among others, fetuses, children, prisoners, pregnant women, mentally disabled persons, and economically or educationally disadvantaged persons. The regulations outline specific provisions for research involving fetuses, pregnant women, and human in vitro fertilization (45 CFR 46 Subpart B); prisoners (45 CFR 46 Subpart C); and children (45 CFR 46 Subpart D). See summary tables for Subpart B (Pregnant Women, Human Fetuses and Neonates), Subpart C (Prisoners) and Subpart D (Children) for additional information. Other populations that should be afforded special consideration include minorities, the terminally ill or institutionalized and the elderly. As of December 13, 2001, revised Subpart B states that the exemptions at 45 CFR 46.101(b)(1) are applicable to Subpart B.

Fetuses, Pregnant Women, and Human In-Vitro Fertilization (45 CFR 46 Subpart B) and (40 CFR Parts 9 and 26)

Research involving the human fetus poses special concerns for investigators and the IRB. The fetus is unique and yet has an inextricable relationship to the mother. A fetus cannot consent to participate as a research subject. In the early 1970's Congress required that the National Commission for the Protection of Human Subjects study the subject of fetal research. The Commission, in its findings, did not define the "personhood" of the fetus; however, it did recognize the genetic heritage and vulnerability of the fetus and affirmed that it should be treated respectfully and with dignity, regardless of its life prospects. The Commission also affirmed the legitimacy and importance of fetal research for improving the health of fetuses both in the present and future. The DHHS has fully implemented the recommendations of the National Commission in 45 CFR 46 Subpart B.  (See Summary Table for Subpart B.)

EPA Final Rule for 40 CFR, Parts 9 and 26 bans research for pesticides involving intentional exposure of human subjects when the subjects are pregnant women or children. Intentional exposure is defined in this rule as exposure they would not have experienced had they not participated in the research. The EPA took this action to ensure that research conducted by EPA or for EPA, submitted to EPA, and relied on by EPA — especially research with human subjects — has been conducted ethically.

In addition to the general requirements for review of research by the IRB, prior research with animal subjects and, if reasonable, research with nonpregnant persons should form the basis of the risk/benefit assessment for fetal research. Investigators who propose research involving human fetuses are required to assure the IRB that they are seeking information not obtainable in any other fashion. More detailed information for conducting fetal research may be found in Federal Regulation 45 CFR 46 Subpart B.

Historically, in order to avert harm to a developing fetus in an unsuspected pregnancy, physicians and the lay community have expressed concerns regarding the participation of women of child-bearing potential in research. As a result, federal agencies developed special guidelines ostensibly for the protection of the developing fetus that excluded women of child-bearing potential from participation in some research. In 1977, for example, the FDA published a guideline that excluded most women of child-bearing potential from early phases of drug trials. An exception was made for studies involving women with serious and life-threatening diseases.

Over the past decade, questions regarding the adequacy and fairness in the distribution of the benefits and risks of research resulted in changes to the regulations for the involvement of women in research. At the same time improved pregnancy tests and methods of contraception became widely available. In 1988, the FDA issued guidelines that called for safety and efficacy profiles for women, elderly, and diverse racial groups as part of new drug applications (NDAs). Then in 1993, following broad public discussion about participation of women in clinical trials, the FDA issued a new guideline that eliminated restrictions on women of child-bearing potential participating in all phases of drug trials. The guideline detailed procedures for minimizing the risks of pregnancy in women participants, such as contraceptive counseling, pregnancy tests, timing of short term studies in relation to the menstrual cycle, and the process of informed consent. Though the FDA emphasized the importance of risk/benefit determinations for subjects entering various phases of clinical trials, they underscored that initial determinations regarding whether risks to a fetus were adequately addressed were best left to patients, physicians, local hospitals, and study sponsors.

The DHHS has also carefully examined the issue of participation of women in research. Since the primary aim of clinical trials is to provide scientific evidence leading to a change in health policy or a standard of care, it is imperative to determine if the intervention or therapy being studied affects men and women differently. As stated in its guideline, "NIH Outreach Notebook of the Inclusion of Women and Minorities in Biomedical and Behavioral Research" (1994) the NIH has concluded that the inclusion of women in research is sufficiently important that the only justifiable reason to exclude nonpregnant women of child-bearing potential from research is compelling evidence that the proposed project would be inappropriate with respect to the health of the subject or the purpose of the research.

The policy statement referenced above pertains primarily to the inclusion of women as subjects in clinical trials, i.e., medical research testing new treatments. However, the inclusion of women in behavioral research is also important and should be accomplished unless there is a compelling rationale which establishes that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research.

Pregnant Women

In accordance with (45 CFR 46.207 [a]), "No pregnant woman may be involved as a subject in a human clinical research project unless: (1) the purpose of the activity is to meet the health needs of the mother and the fetus will be placed at risk only to the minimum extent necessary to meet such needs, or (2) the risk to the fetus is minimal."

Research involving pregnant women is permitted only if the mother and father are legally competent and both have given their consent after having been fully informed regarding the possible impact on the fetus, except that the father's consent need not be secured if (1) the purpose of the activity is to meet the health needs of the mother; (2) his identity or whereabouts cannot reasonably be ascertained; (3) he is not reasonably available; or (4) the pregnancy resulted from rape (45 CFR 46.207 [b]).

Women of Childbearing Potential

Nonpregnant women should not be excluded from any phase of research unless the science of the project or the health of the subject will be compromised. Regarding clinical drug research, Phase I, II and III trials should have the proportion of women in the study which at least reflects the proportion of women in the population which will receive the drug when it is marketed, and should enroll numbers adequate to detect clinically significant sex differences in drug metabolism and response.

Risk to Fetus and/or Infant

In accordance with Federal Register guidelines (Vol.58, No. 139, p39411, Thursday, July 22, 1993), "Appropriate precautions should be taken in research studies to guard against inadvertent exposure of fetuses to potentially toxic agents and to inform subjects and patients of potential risk and the need for precautions. In all cases, the informed consent document and investigator's information brochure should include all available information regarding the potential risk of fetal toxicity. If animal reproductive toxicity studies are complete, the results should be presented, with some explanation of their significance in humans. To minimizing the possibility of fetal exposure, testing may be used to detect unsuspected pregnancy prior to initiation of study treatment.

Minorities

In addition to requiring the equitable selection of women as research subjects, federal regulations require the equitable selection of minorities as research subjects (45 CFR 46.111.[a][3]). The inclusion of minorities in research is important both to make sure they receive an equal share of the benefits of research and do not bear a disproportionate burden.

Most diseases affect all population groups. In order to contribute to the pool of generalizable knowledge, investigators are required to include the widest possible range of population groups in their research. However, sometimes minorities are subject to a different risk. For example, some research pertains to conditions such as sickle cell anemia or Tay Sachs disease that specifically affect only a few minority groups. Other research focuses on characteristics of diseases or effectiveness of therapies in particular populations (e.g., HIV transmission, treatment for hypertension), and may also concern conditions or disorders that disproportionately affect a certain racial or ethnic group. Exclusion or inappropriate representation of these groups, by design or inadvertence, would be unjust. Further, to the extent that participation in research offers direct benefits to the subjects (in HIV research, for example, the receipt of a promising new drug), under-representation of minorities denies them, in a systematic fashion, the opportunity for direct benefit. A glaring example of this type of research abuse of minority populations' bearing the burden of research can be found in the Tuskegee Syphilis study, in which a group of African-American men suffering from syphilis were left untreated, despite the availability of penicillin, in order to study the natural course of the disease.

Due to these concerns, the federal regulations require that research design include diverse populations. Investigators submitting protocols for IRB review which do not call for heterogeneous study populations are required to justify, in writing, in their submissions, why a homogeneous study population has been chosen.

After a heterogeneous population has been chosen, investigators should pay careful attention to the following two issues:

  1. Special Vulnerabilities: The DHHS recognizes that certain subject populations may require additional protections because they are economically or educationally disadvantaged. The IRB will attempt to safeguard every subject's rights and welfare by making sure that any possible coercion or undue influence is eliminated (e.g., compensation that is not commensurate with risk, discomfort, or inconvenience involved, or recruiting in institutional settings where voluntary participation might be compromised). Investigators should address these issues specifically when submitting protocol information to the IRB for review.
  2. Consent Form Presentation: Effort should always be made to make sure that the consent process and the relationship between the investigator and prospective subjects are safeguarded. The federal regulations require the translation of consent documents into the language which is most easily understood by research subjects; the possibility of illiteracy should be accounted for, as should the need for communicating in non-English languages. The FDA indicated in October 1995, that non-English speaking subjects must have informed consent form information presented in a written language that they understand. A potential subject's inability to read or to read English is not an appropriate basis for exclusion from most research.

The IRB approved informed consent documents should be available in English and other languages as appropriate to the subject population(s). For investigators proposing to use non-English language consent documents, quality assurance procedures should be developed such as translation of the consent document from English to the second language and then back to English, to confirm that the information is correctly conveyed. The IRB is required to review all non-English consent forms and recruitment tools. The role of cultural norms of subjects should also be addressed.

Prisoners (45 CFR 46, Subpart C)

Prisoners are considered vulnerable because they are in a restrictive, institutional environment that affords little opportunity for making choices, earning money, communicating with outsiders, or obtaining medical care. The National Commission for the Protection of Human Subjects found that prisoners often volunteer for medical research as a means of access to a competent medical examination, because health care is woefully inadequate in most prisons. (See Summary Table for Subpart C.)

Because their autonomy is limited, prisoners may participate only in certain categories of research, and special precautions are needed to assure that their consent to participate in the research is both knowing and voluntary.

Categories of Research in Which Prisoners May Participate

Prisoners may participate in the following kinds of research:

  1. Studies of the possible causes, effects, and process of incarceration and criminal behavior, if those studies present no more than minimal risk or inconvenience to the subjects;
  2. Studies of prisons as institutions, or of prisoners as incarcerated persons, if those studies present no more than minimal risk or inconvenience to the subjects;
  3. Research on conditions affecting prisoners as a class (e.g., research on hepatitis, drug addiction, sexual assaults, and other conditions more prevalent in a prison population than elsewhere), but only after the Secretary, HHS, has consulted with experts in medicine, ethics, and penology and published a notice approving the proposed research in the Federal Register; and
  4. Research on practices that are intended, and reasonably likely, to enhance the well-being of the subjects; however, if some of the prisoners will be assigned to control groups which will not benefit from the research, then the study must first be approved by the Secretary, HHS, after consultation with appropriate experts, as described above.

When the IRB reviews research that will involve prisoners they are required to first confirm that the proposed study fits within one of the permissible categories of research described above. Then, it must determine:

Children (45 CFR 46, Subpart D)

Special considerations apply when research involves subjects who are children (in Washington, under 18 years of age) as they are inherently more vulnerable than adults and require a higher level of protection.

Federal regulations for research with adult subjects (Title 45-Code of Federal Regulations (CFR)-Part 46) serve as a starting point. Additional special considerations for children are outlined in 45 CFR 46, Subpart D and 21 CFR 50 for FDA-regulated research. (See Summary Table D for additional information.)

EPA Final Rule at 40 CFR, Parts 9 and 26 bans research for pesticides involving intentional exposure of human subjects when the subjects are pregnant women or children. Intentional exposure is defined in this rule as exposure they would not have experienced had they not participated in the research. The EPA took this action to ensure that research conducted by EPA or for EPA, submitted to EPA, and relied on by EPA — especially research with human subjects — has been conducted ethically.

Studies Involving Children

When planning a study that will involve children, the principal investigator (PI) should first consider four main issues:

  1. What is the rationale for including children? What unique outcomes, benefits, and risks will come from studying children? Does the study address a condition that particularly affects children?
  2. How is the study risk level determined? What are the relevant regulations?
  3. How are study procedures different from standard of care for the subjects?
  4. What are consent (permission and assent) requirements for the study? Will permission from one or both parents be needed?

Rationale for Inclusion of Children in Research

As in any human research application, the choice of subject population must be explained. The investigator should analyze what is unique to children in formulating this rationale, as well as in assessing the risks and benefits of the study (see below).

The rationale for including children in a study should be described in the application for review and in the consent and assent forms. Examples of appropriate rationales for inclusion of children in research include:

The research holds out the prospect of benefit to children and involves:

Permitted Categories for Research with Children

The following information is from the US Code of Federal Regulations (CFR) regarding the four permitted categories of research with children. For complete requirements, see the Additional DHHS Protections for Children exhibit. When reviewing research involving children, the IRB must document the appropriate risk/benefit category.

  1. Minimal Risk (45 CFR 46.404)
    • Description: "Research not involving greater than minimal risk."
  2. Greater than Minimal Risk, Direct Benefit to Subject (45 CFR 46.405)
    • Description: "Research involving greater than minimal risk, but presenting the prospect of direct benefit to the individual subjects."
  3. Greater than Minimal Risk, No Direct Benefit to Subject, but Likely to Yield Generalizable Knowledge about Subject's Condition (45 CFR 46.406)
    • Description: "Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about subject's disorder or condition...the risk represents a minor increase over minimal risk."
  4. Greater than Minimal Risk, No Direct Benefit to Subject, but Results May Alleviate Serious Problems of Children's Health or Welfare (45 CFR 46.407)
    Note: Category 4 (45 CFR 46.407) type of study is very rarely approved.
    • Description: " Research not otherwise approvable which presents opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children."

Students, Military Personnel, Workers and Employees

Students, workers, employees and military personnel may feel (or actually be) vulnerable or restricted in their ability to decline participation in a research study; particularly when the person recruiting them is in a position of power or influence over their future employability or chance for promotion. When the potential for coercion or undue influence exists, perceived or otherwise, PIs and the IRB must carefully assess the situation and confirm that every measure is taken to promote true voluntariness in the recruitment and treatment of these subjects.

Students

Medical students traditionally have served as subjects for biomedical research and psychology students have often participated as subjects in behavioral research. The obvious concern is that their participation may not be truly voluntary, because of a desire to appear particularly cooperative or highly motivated, or because participation in research is a course requirement.

Various procedures have been suggested to reduce the possibility of unintended coercion, while still permitting students to participate as subjects in research. These include:

Military Personnel

The military sometimes perceive the use of their personnel as subjects of research differently than IRBs do. They might, for instance, consider it a soldier's duty to participate in an activity that had the potential to protect them in a time of war, such as an inoculation for anthrax and they would not consider that decision to be coercive or unduly influencing.

Each study is reviewed by the IRB according to its own merits but, in general, when PNNL collaborates in low risk research involving military personnel, these differences are taken into account and a best effort is made to make sure participation is voluntary and all communication between the collaborating institutions is documented to the files. If the IRB determines that the risk to military personnel is unacceptable and believe that no attempt has been made to minimize that risk, PNNL's participation in the study will not be approved by the IRB.

Workers and Employees

Employees of an institution are similar to students in that they are vulnerable to perceived, even if not intended, pressures to appear cooperative and supportive of their peer or supervisor's work or institutional goals. Accordingly, many of the same procedures (described above) to reduce the likelihood of coercion in recruiting student volunteers apply equally to PNNL employees. It is generally IRB policy not to approve recruitment procedures that include employees from the investigator's own lab or office. The IRB, however, will consider this policy on a case by case basis.

Battelle Staff and Family Members

The use of Battelle staff or their families as subjects of research requires an exception to Battelle Corporate Policy 1.1.1.6, and approval by the IRB and the Laboratory Director. Only those activities determined by the IRB to be of minimal risk or less will be considered. To obtain approval, PIs must clearly justify, in their application for review, why Battelle staff or their family members are required to accomplish their work and document why it would be impracticable to use other members of the community as volunteers. Ease of access is not a valid reason.

Investigators must also describe the method(s) that will be employed to confirm that participation of Battelle staff or their families will be accomplished in a fully voluntary manner without undue influence or risk of coercion, perceived or otherwise, and they must demonstrate how the privacy of the subjects will be fully protected. PIs may apply for an exception to Corporate Policy 1.1.1.6 as part of their applications for review. If approved by the IRB, the request for use of Battelle staff or their immediate family members will be forwarded to the Institutional Official for final approval. The PI, who will be notified of the IRB's decision via the standard IRB approval notification, has the right of appeal in accordance with policies and procedures provided in the Questions, Concerns and Complaints section of this web site. Immediate family members include a spouse, domestic partner, parent, children and dependents.

Secondary Subjects/Family Members

A fundamental principle of human subject research is that the research should not place individuals at risk of harm without explicit informed consent. Current standards and regulations have considered research subjects either an autonomous individuals capable of making decision, or as incompetent persons for whom other safeguards must be employed to properly allow their inclusion in research activities. Obligations to protect privacy and confidentiality are inherent in our informed consent practices and dealings with these individuals. Consideration regarding individuals linked to research subjects through family or social relationships must also be provided.

In an effort to help maintain the safety, security and privacy of not only those individuals directly participating in studies by those linked or related to them, PNNL requires its PIs to see to it that adequate consideration has been given to family members or "secondary subjects."

PIs should ask themselves the following questions:

  1. Are family members secondary subjects of this research?
  2. Are family members readily identifiable by the researchers?
  3. Does the information obtained from primary subjects about family members constitute private information?
    • Yes, if the information consists of health status, health, reproductive or behavioral history.
    • No, if the information consists only of the family relationship and commonly available personal data such as age, race, or occupation.
  4. If family members are considered secondary human subjects, can consent be waived?
    • Does the research involve more than minimal risk?
    • Would a waiver adversely affect the rights and welfare of the subjects?
    • Can the research practicably be carried out without the waiver?
    • When appropriate, will secondary subjects be provided with pertinent information at project completion?