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Ethical perspectives of children's assent for research participation: deontology and utilitarianism.

The study of children has intrigued researchers since ancient times. Ethical dilemmas of such research can be seen in the exemplars listed in Table 1. In some studies (such as the smallpox vaccination research and studies conducted by Joseph Goldberger), children had the potential to directly benefit. However, in the examples of the Persian fable, the Willowbrook Hospital, and the Turkish newborn, no potential benefit to participating individuals existed (see Table 1).

Definition of terms. For the purposes of this article, the term parent is used to designate any legal guardian. The term permission is used when an individual allows another person with legal responsibility to participate; the term consent is restricted to individuals who are legally able to do so agrees to his or her own participation. The term assent is used when a child agrees to his or her own participation. The institutional Review Board (IRB) is the legally mandated group of reviewers who oversee a researcher's plan of study and ensure no harm will come to the human subjects participating in the study.

Mandates to protect children as research subjects. The outcry following the discovery of studies conducted by Nazi physicians to benefit the Third Reich resulted in 10 requirements for research in humans known as the Nuremburg Code (1949). The mandates that protect children as research participants internationally and those specific to the United States are located in Tables 2 and 3, respectively. As an indication of how the issue of conducting research with children has evolved since their exclusion in the Nuremberg Code, children are not only included as a vulnerable population entitled to extra protection, but Guideline 14 of the Council for International Organizations of Medical Sciences (CIOMS) (2002) report is entitled "Research Involving Children."

Research involving children. The United States Department of Health and Human Services published what is known as the Common Rule in 1973 (U.S. Department of Health and Human Services, 2005). However, it was not until a decade later that Subpart D, Additional Protections for Children Involved as Subjects in Research (see Table 3), was issued (Institute of Medicine [IOM], 2004).

The most recent report was published by the IOM in 2004. This comprehensive report provides direction for researchers whose studies involve children regarding applicable regulations within the United States, determination of risks and benefits, comprehension of the meaning of a child's participation in research by parents and children, and payment for a child's participation in research. It also provides insight into the mechanisms of regulatory compliance and functions of IRBs relative to research involving children. However, there are still areas that are interpreted differently depending on the particular ethics review committee or IRB involved, and further clarification to promote consistency across institutions would be beneficial.

Ethical Positions

"Ethically, the obligation to act in a child's best interest entails protecting children from both the potential risks of research and the harms produced by the use of inadequately tested [treatments], as well as respecting their autonomy" (Sutcliff, 2003, p. 65). The ethical theories that will be used to support and oppose the ethical mandate that a child's assent to participate in research that does not have the potential to directly benefit the child are deontology and utilitarianism.

Deontoiogy. The non-consequentialist theory of deontology is derived from the writings of German philosopher Immanuel Kant (1724-1804). Kant stated that a universal law should provide the basis for each act, and that the intent was of more importance than the outcome. Deontology is a duty-based ethical stance, where one's actions are based on what is morally correct, irrespective of the consequences.

This theory requires that individuals be treated as an end in themselves and never as a means to an end. From this viewpoint, the only research with children that is ethically acceptable is that which has the potential to benefit the child or when the child is capable of assent. Proponents of deontology would carefully evaluate any research in which the child was used as a means to an end for another purpose. Attempts are made to address the need to respect a child's autonomy by obtaining assent from those children capable of providing it. However, awareness of the morally correct choice for a particular child in a specific situation requires a certain level of cognitive development that not all children have achieved. In addition, the age at which a person is no longer considered a child, and thus, the age at which Subpart D of the Code of Federal Regulations no longer applies, varies depending on state law within the U.S.; although, in the vast majority of states, that age is 18 (Campbell, 2004). Parents must give permission to have their child participate in research. Requirements become less clear in research involving adolescents who are emancipated minors or in cases related to pregnancy or social stigma (such as substance abuse, human immunodeficiency virus [HIV] or acquired immune deficiency syndrome [AIDS], sexually transmitted diseases, or mental health issues) (Campbell, 2004). Therefore, each individual IRB must decide when an adolescent is able to consent to his or her own participation in research.

IRBs must also decide how to interpret [section] 46.408 of the Code of Federal Regulations, where the instructions for establishing criteria for children's assent to participate in research state that "the IRB shall take into account the ages, maturity, and psychological state of the children involved." Interviews of chairpersons were conducted to ascertain how their IRBs determined which children were capable of assent (Whittle, Shah, Wilfond, Gensler, & Wendler, 2004). Ninety-one (48%) of the 188 IRB chairpersons used one or more specified criteria. Of the 88% that included an age requirement, 6% required that assent be obtained from children five years of age and 14% from children 10 years of age. Seven years of age was cited by 46% of the chairpersons from IRBs that had an age requirement for assent. Only one institution used a cognitive test to determine the capacity of a child to provide assent. Investigator judgment was a determining factor as to whether or not a child was capable of providing assent in 25% of IRBs with specified criteria and 68% of IRBs without specified criteria.

Assent requirements of 55 IRBs were compared using 69 study approval documents for one or more of three multicenter pediatric clinical trials (Kimberly, Hoehn, Feudtner, Nelson, & Schreiner, 2006). In 31 of the approval documents, there were specific ages at which assent was to be obtained. The minimum age of children from whom assent was obtained in 21 of the studies was 7 years of age; others varied from 6 years of age (3), 9 years (2), 12 years (2), 13 years (2), to 15 years (1). However, 14 years is the age at which most children have moral reasoning ability that allows them to help others without the expectation of any personal consequences (Wendler, 2006). Kon (2006) suggests that "assent policies must be rigid enough to provide protection and respect for children yet flexible enough to allow for varied cognitive and emotional levels, and to appropriately address the diverse preferences of our potential pediatric research subjects" (p. 1808).

A child's ability to understand what participation in a particular study would mean to him or her not only depends on characteristics related to the individual child, but also on the complexity of the study. However, while investigator judgment may be the most appropriate way to meet the Code of Federal Regulations requirements for assent in each particular study, it increases the importance of IRB assurance that investigators have appropriate pediatric expertise. From the ethical perspective of deontology, children must not be exposed to harm for the benefit of others. This perspective mandates assent from a child in order to participate in research that does not have the potential to directly benefit that particular child.

Utilitarianism. Utilitarianism is one of the major teleological, or consequentialist, theories and is derived from the works of Jeremy Bentham (1748-1832) and John Stuart Mill (1806-1873) (Beauchamp & Childress, 2001). It deems that the determination of whether or not actions are correct depends on the overall balance between risks and benefits resulting from that action. Neutel quotes from the 1994 Collins English Dictionary and Thesaurus that "utilitarianism is 'the doctrine that the morally correct course of action consists in the greatest good for the greatest number, that is, in maximizing the total benefit resulting without regard to the distribution of the benefits and burdens'" (Neutel, 2004, p. 119). Research that is more beneficial to many children than harmful to the pediatric participants involved is justified from the utilitarian ethical perspective, and thus, assent is not mandated. Children often have been denied the benefits of research advancements because of restrictions against their participation in research. Dosages of medications that have not been evaluated in children are chosen anecdotally or by estimations based on those determined to be therapeutically optimal in research involving adults. However, the pharmacokinetics and pharmacodynamics often differ depending on the age and developmental stage of a child. Thus, children may not absorb, metabolize, and excrete medications using the same pathways or at the same rates, nor respond in the same manner as their adult counterparts in whom the medications have been studied. Children may also be born with congenital anomalies or be subject to unique disease processes and metabolic derangements. In the past, children have been subject to risks related to scientific advances that are now taken for granted and from which today's children benefit, such as immunizations against common childhood illnesses that in previous generations often caused significant mortality.

If systematic determination of that which is most beneficial to children who are unable to provide assent to participate in research is to occur, studies in which they partake must be conducted, even when the research involves greater than minimal risk and will not directly benefit the pediatric participants. Based on the principle of distributive justice, it is unethical for children to be excluded from the benefits of scientific advances made as a direct result of research as compared to their adult counterparts.

However, this framework requires that children be exposed to associated risks, some of which are greater than minimal. Every effort must be made to prevent exposure to unnecessary risks by having pediatric specialists conduct well-designed research that is carefully monitored by an IRB and has an adequate sample size to make the results meaningful. Participants need to be observed for signs of distress and allowed to dis-enroll from the study at any point without negative consequences.

If children unable to give assent are excluded from being research participants, childhood treatment based on anecdotes or the results of studies conducted with adults, such as "off-label" use of medications, may result. In these situations, children are exposed to risks that are not controlled and do not have the benefit of the systematic evaluation that occurs in a research environment.

Conclusion

Although not all children would choose to participate in research that has no possibility of benefitting them personally if they had the capacity to assent, some would want that opportunity. By preventing all from participating, the respect for autonomy among those who would choose to participate is ignored. Thus, from the ethical perspective of utilitarianism and in combination with the requirement of parental permission and

provided IRB safeguards, children should be allowed to participate in research when they are unable to assent. Thus, the answer to the question of whether a child's assent to participate in research that does not have the potential to directly benefit the child is ethically mandated depends on the ethical perspective from which it is viewed, with that of utilitarianism being the currently more widely accepted perspective.

Acknowledgment: The author would like to thank Dr. Andrea Gregg, Fern Hannigan, MSN, and Dr. Anita Catlin for reviewing this manuscript and providing suggestions for its improvement.

References

Beauchamp, T.L., & Childress, J.F. (2001). Principles of biomedical ethics (5th ed.). New York: Oxford University Press.

Campbell, A.T. (2004). State regulation of medical research with children and adolescents: An overview and analysis. In M.J. Field & R.E. Behrman (Eds.), Ethical conduct of clinical research involving children (pp. 320-387). Washington, DC: National Academies Press.

Council for International Organizations of Medical Sciences (CIOMS). (2002). International ethical guidelines for biomedical research involving human subjects [Electronic version]. Geneva Switzerland: Author.

Giantz, L.H. (1996). Conducting research with children: Legal and ethical issues. Journal of the American Academy of Child and Adolescent Psychiatry, 35, 1283-1291.

Institute of Medicine (IOM). (2004). Ethical conduct of clinical research involving children. Washington, DC: National Academies Press.

Jonsen, A.R. (1978). Research involving children: Recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Pediatrics, 62, 131-136.

Kimberly, M.B., Hoehn, K.S., Feudtner, C., Nelson, R.M, & Schreiner, M. (2006). Variation in standards of research compensation and child assent practices: A comparison of 69 Institutional Review Board-approved informed permission and assent forms for 3 multicenter pediatric clinical trials. Pediatrics, 117(5), 1706-1711.

Kon, A.A. (2006). Assent in pediatric research. Pediatrics, 117(5), 1806-1810.

Kopelman, L.M. (2004). Minimal risk as an international ethical standard in research. Journal of Medicine and Philosophy, 29, 351-378.

Lederer, S.E., & Grodin, M.A. (1994). Historical overview: Pediatric experimentation, in M.A. Grodin & L.H. Glantz (Eds.), Children as research subjects: Science, ethics, and law (pp. 3-25). New York: Oxford University Press.

Mastroianni, A.C., & Kahn, J.R (2002). Risk and responsibility: Ethics, Grimes vs. Kennedy Krieger, and public health research involving children. American Journal of Public Health, 92, 1073-1076.

National Institutes of Health (NIH). (1998). NIH policy and guidelines on the inclusion of children as participants in research involving human subjects. Retrieved June 22, 2008, from http://grants.nih.gov/grants/ guide/notice-files/not98-024.html

Neutel, C.I. (2004). The dilemma of using humans as research subjects: An assessment of risks and benefits. Drug Information Journal 38, 113-126.

Nuremberg Code. (1949). Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10 (Vol. 2, pp. 181-182). Washington, DC: U.S. Government Printing Office, Retrieved June 22, 2008, from http://www.hhs. gov/ohrp/references/nurcode.htm

Rosner, F. (2006). Medical research in children: Ethical issues. Cancer Investigation, 24, 218-220.

Sutcliffe, A.G. (2003). Testing new pharmaceutical products in children. British Medical Journal 326(7380), 64-65.

Ulusoy, M.F. (1998). "Waiting in Araf": Research without consent: A Turkish mother's experience. Pediatric Nursing, 24, 562-564.

U.S. Department of Health and Human Services (DHHS). (2005). Code of Federal Regulations: Title 45, Part 46. (2005). Retrieved September 5, 2007, from http://www.hhs.gov/ohrp/documents/OHRPRegulations.pdf

U.S. Food and Drug Administration (FDA). (2002). Best Pharmaceuticals for Children Act, Pub. L. No. 107-109. Retrieved July 10, 2008, from http://www.fda.gov/opacom/laws/pharmkids/contents.html

Wendler, D.S. (2006). Assent in paediatric research: Theoretical and practical considerations. Journal of Medical Ethics, 32(4), 229-234.

Whittle, A., Shah, S., Wilfond, B., Gensler, G., & Wendler, D. (2004). Institutional Review Board practices regarding assent in pediatric research. Pediatrics, 113(6), 1747-1752.

World Medical Association Declaration of Helsinki. (2004). Ethical principles for medical research involving human subjects. (Guideline 24). Retrieved June 22, 2008, from http://www.wma.net/e/ policy/pdf/17c.pdf

Pam Pieper, MSN, ARNP, PNP-BC, is a Pediatric Nurse Practitioner, a Clinical Nurse Specialist, and a Clinical Associate Professor, the University of Florida College of Nursing, Jacksonville, FL, and a Doctoral Student, Barry University, Orlando, FL. She is a Charter Member and Past President of the American Pediatric Surgical Nurses Association (APSNA).
Table 1.
Historical Exemplars of Pediatric Ethical Dilemmas

   Year            Exemplar

Fable         Persian prince isolated newborns from sounds of human
              speech to investigate language development (Jonsen,
              1978).

1802          Smallpox vaccination given to 48 children in British
              foundling home before given to children of Queen
              Caroline (Jonsen, 1978; Glantz, 1996).

Early 1900s   Joseph Goldberger (for the U.S. Public Health Service)
              gave fresh vegetables, eggs, and milk to children
              living in orphanages in Mississippi and then other
              southern states (Lederer & Grodin, 1994).

Early 1900s   Alfred Hess (pediatrician) conducted research at the
              Hebrew Infant Asylum in New York City because he was
              better able to control extraneous variables than in
              non-institutional settings (Lederer & Grodin, 1994).

1950s-1970s   Saul Krugman infected institutionalized mentally
              handicapped children at Willowbrook Hospital (Staten
              Island, New York) with hepatitis to observe disease
              progression. Originally, parents had a choice of
              units, but when other units reached capacity, they
              could only be admitted if they agreed for the child
              to be on the research unit (Glantz, 1996; Rosner,
              2006).

1970s         Suspected research on a healthy newborn in Turkey
              without parents' knowledge (Ulusoy, 1998).

2001          Grimes vs. Kennedy Krieger Institute: Study of
              different levels of lead abatement in housing
              projects in Baltimore, MD (Mastroianni & Kahn,
              2002).

              Ethical Principle     Ethical Principle
   Year        Used to Justify           Violated

Fable         Utilitarianism       Beneficence
                                   Respect for autonomy

1802          Utilitarianism       Distributive justice
                                   Non-maleficence
                                   Respect for autonomy

Early 1900s   Non-maleficence      Distributive justice
              Utilitarianism       Respect for autonomy

Early 1900s   Utilitarianism       Distributive justice
                                   Respect for autonomy

1950s-1970s   Utilitarianism       Distributive justice
                                   Non-maleficence
                                   Respect for autonomy

1970s         Utilitarianism       Non-maleficence
                                   Respect for autonomy

2001          Beneficence          Distributive justice
              (parental consent)   Non-maleficence
              Utilitarianism       Respect for autonomy

Table 2.
International Mandates to Protect Children as Research Participants

Year        Mandate                     Pediatric Features

1947   Nuremberg Code       "Voluntary consent of the human subject is
                            absolutely essential" (Nuremberg Code,
                            1949), excluding all children from research
                            participation. This requirement, among
                            other aspects of the Code, was ignored in
                            the United States.

1964   Declaration of       Research must have the potential to benefit
       Helsinki             study participants (Kopelman, 2004).

2000   Declaration of       Research must "promote the health of the
       Helsinki             population represented, and this research
       (revision)           cannot instead be performed on legally
                            competent persons" (World Medical
                            Association Declaration of Helsinki, 2004).

                            Requires parental permission and assent
                            from all children capable of making the
                            decision.

2002   International        For those incapable of giving consent: If
       Ethical Guidelines   research offers no potential to benefit
       for Biomedical       study participants, the risk involved
       Research Involving   cannot be greater than that of "routine
       Human Subjects       medical or psychological examinations of
       (CIOMS)              such persons" (CIOMS, 2002).

                            May be allowed to have slightly greater
                            risk "when there is an overriding
                            scientific or medical rationale" (CIOMS,
                            2002) for the increased risk and the study
                            is approved by an ethical review committee.

                            Guideline 9, Special limitations on risk
                            when research involves individuals who are
                            not capable of giving informed consent
                            Research must (a) be relevant to child's
                            medical condition, (b) involve risks
                            similar to those the child has or will
                            likely be exposed to during treatment for
                            the condition, and (c) if child becomes
                            capable of providing informed consent,
                            it will be obtained before proceeding
                            further with the study.

                            Guideline 14, Research involving children:
                            (a) Research cannot be accomplished as well
                            using adults; (b) rational is to increase
                            understanding of a pediatric health care
                            issue; (c) permission has been granted by
                            child's parent; (d) child, to extent of
                            possible, has given assent; and (e) should
                            the child decide not to continue with the
                            research at any point, researchers will
                            comply with that decision. Commentary on
                            this guideline includes that "older
                            children, who are more capable of giving
                            assent, should be selected before younger
                            children or infants, unless there are valid
                            scientific reasons related to age for
                            involving younger children first" (CIOMS,
                            2002).

Table 3.
American Mandates to Protect Children as Research Participants

Year         Mandate                     Pediatric Features

1983   Code of Federal        Distinctions between four degrees of
       Regulations, Title     research risks and criteria that must
       45, Part 46,           be met for each:
       Subpart D:
       Additional             [section] 46.404: No more than minimal
       Protections for        risk.
       Children Involved
       as Subjects in         [section] 46.405: More than minimal
       Research (U.S.         risk, but "prospect of direct benefit
       Department of          to the individual subjects" (DHHS,
       Health and Human       2005).
       Services, 2005)
                              [section] 46.406: More than minimal
                              risk without possibility of benefit to
                              participants, but "likely to yield
                              generalizable knowledge about the
                              subject's disorder or condition"
                              (DHHS, 2005).

                              [section] 46.407: "Research not
                              otherwise approvable, which presents
                              an opportunity to understand,
                              prevent, or alleviate a serious problem
                              affecting the health or welfare of
                              children" (DHHS, 2005).

                              Studies meeting [section] 46.404 and
                              46.405 criteria may only require one
                              parent's permission at individual IRB
                              discretion, but when both parents are
                              the child's legal guardians, both must
                              give permission for [section] 46.406
                              and 46.407 studies.

1998   NIH Policy and         Goal to increase research involving
       Guidelines on the      children: All human research sponsored
       Inclusion of           or conducted by NIH must include
       Children as            children unless specific exclusion
       Participants in        criteria are met.
       Research Involving
       Human Subjects         Must also include (a) research team
       (National Institutes   members with pediatric expertise
       of Health [NIH],       relative to included age groups, (b)
       1998)                  pediatric appropriate facilities, and
                              (c) sufficient sample size to meet
                              study purposes.

2002   Best                   Goal to make medications safer and
       Pharmaceuticals for    more effective for children.
       Children Act (U.S.
       Food and Drug
       Administration
       [FDA], 2002)

2004   IOM Report: Ethical    Three main areas of emphasis: (a)
       Conduct of Clinical    "Well-designed and well-executed
       Research Involving     clinical research involving
       Children (IOM,         children is essential to improve the
       2004)                  health of future children--and future
                              adults--in the United States and
                              worldwide" (IOM, 2004), (b) there must
                              be additional research protections for
                              children beyond those required for all
                              human research subjects, and (c) those
                              who are involved with pediatric
                              research at any level must have
                              acknowledged pediatric competency.
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Title Annotation:Pediatric Ethics, Issues, & Commentary
Author:Pieper, Pam
Publication:Pediatric Nursing
Geographic Code:1USA
Date:Jul 1, 2008
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