Participation in biomedical research: The consent process as viewed by children, adolescents, young adults, and physicians E l i z a b e t h J. S u s m a n , PhD, RN, L o r a h D. Dorn, PhD, RN, a n d J o h n C. F l e t c h e r , PhD* From the Laboratory of Developmental Psychology, National Institute of Mental Health, and the Clinical Center, National Institutes of Health, Bethesda, Maryland
We examined the c a p a c i t y of children, adolescents, and young adults to assent and consent to participation in biomedical research, and what physicianinvestigators believe is important for patients in these a g e groups to know about such participation. The sample included 44 male and female subjects, ranging in a g e from 7 to 20 years, who were hospitalized to treat either pediatric c a n c e r or obesity. The participants c o m p l e t e d a structured interview that assessed knowledge of research participation using the elements outlined in the federal guidelines for informed consent. The study subjects were most k n o w l e d g e a b l e about those elements of consent that assessed concrete information (e.g., freedom to ask questions, time elements involved, and the benefits of participation). They were less k n o w l e d g e a b l e about those elements of informed consent that assessed abstract information (e.g., scientific vs therapeutic purpose of the study, and alternative treatments). Chronologic a g e was not related to knowledge of the elements of informed consent. The strategies that the study subjects used to reason about participation in research a p p e a r e d to parallel their reasoning about other physical phenomena. (J PEDIATR1992;121:547-52)
Children's participation in biomedical and behavioral research presents ethical dilemmas for researchers as well as for the parents who provide legal permission for their children to participate. Only recently have studies begun to examine children's understanding of human experimentation, 1,2 their capacity to consent,3 and developmental differences in their capacity to consent to research participation.4, 5 In the situations examined, children can partic-
Supported in part (L.D.D.) by a National Research Service Award (SRC-5-F31-NR05965) from the National Center for Nursing Research, National Institutes of Health. Submitted for publication Feb. 26, 1992; accepted May 20, 1992. Reprint requests: Elizabeth J. Susman, PhD, E-314 Health and Human Development Bldg., Pennsylvania State University, University Park, PA 16802. *Now at the University of Virginia School of Medicine, Charlottesville. 9/20/39511
ipate in some aspects of the consent process. To our knowledge, no empiric studies have examined the consent process for children who participate in biomedical research. Among adults, knowledge of experimental treatment-the essence of informed consent--improved when consent forms were shorter or when less information was provided in the forms, 6-8 when the consent form was sent home before the procedure, 9 and when participants had a good vocabulary. 1~ Studies also have revealed that adult patients are not well informed about the nature of clinical research participation,11-13 and parents are not well informed about the nature of their child's participation in research. 14 This less-than-optimal knowledge about research participation exists in spite of regulations requiring that informed consent be obtained from subjects over the age of majority. In the informed consent process, the patient must be given an explanation of the nature and purpose of the research; the procedures used, including those experimental in nature; the short- and long-term risks and discomforts; and the 547
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anticipated benefit to self and others. In addition, alternative treatments and the duration of the research must be disclosed, and the patient must be given freedom to ask questions at any time and freedom to withdraw from the research. Acting on recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 15, 16 the federal government also formulated regulations about the necessity of obtaining children's assent to participate in research. 17 These regulations state that when research involves a child aged 7 years or older, legal permission must be obtained from the parent or guardian and assent must be obtained from the child. Each institutional review board has the responsibility to determine the necessity of obtaining assent from children enrolled in a protocol. The regulations also state that age, maturity, and psychologic state should be considered in the determination of whether children are capable of assenting to participation in research. We sought to examine the capacity of children, adolescents, and young adults to assent and consent to participation in research. Our aim was to generate findings that could help protect children from an inappropriate degree of inclusion or exclusion in the assent process. Because cognitive abilities increase with age, we expected that the capacity to comprehend more about research participation would be greater in older children, adolescents, and young adults than in younger children. We also examined what physician investigators believe is important for children and adolescents to know compared with what our study subjects actually knew about participation in research. METHOD Participants. Forty-four male and female subjects ranging in age from 7 to 20 years participated in the study. These ages were included because guidelines for research with human subjects suggest that children younger than age 7 years cannot assent to research, and because adolescents and young adults up to age 21 years represent the oldest age group in many pediatric settings. Legally, anyone 18 years of age or older is an adult for purposes of health care consent. 18 Children, adolescents, and young adults in our study were from skilled worker or managerial level homes as determined by the family occupational and educational levels. 19 Participants consisted of two patient groups admitted for the first time to a research institution. Approval for our study was obtained from the institutional review board where the data were collected~ . The first group of patients consisted of 11 female and 9 male subjects receiving experimental treatment for pediatric cancers (age range, 7 to 20 years; mean [+_SD] age, 14.6 + 3.9). The diagnoses were Ewing sarcoma, n = 6; Burkitt lymphoma, n = 5; rhabdomyosarcoma, n = 3; os-
The Journal of Pediatrics October 1992
teogenie sarcoma, n = 1; acute lymphocytic leukemia, n = 1; and lymphomas or soft tissue tumors, n = 4. Cancers were newly diagnosed in 17 patients, and no treatment had been given elsewhere for their disease. Eleven patients had been hospitalized previously for their current disease, but hospitalization had been primarily for diagnostic rather than for treatment purposes. For all participants, the current hospitalization was their first admission to a research hospital. The second group of patients consisted of 21 girls and 3 boys who were receiving treatment for obesity (age range, 7 to 17.3 years; mean [ +_SD] age, 13.9 ___ 2.6 years). Children and adolescents in this group were hospitalized as inpatients for 3 weeks on a unit primarily housing children with endocrine disorders and obesity. All patients weighed at least 50% more than the ideal body weight according to height-for-weight standards. The ratio of girls to boys in the sample is representative of the numbers referred for obesity treatment in the institution. Procedures. After being enrolled in a medical protocol, all eligible patients and their parents were approached by the investigators and given verbal and written explanations of this study. Questions were answered and the informed consent or assent form was given to patients who met the criteria for participation. A few days later the investigators returned to review the study and answer any questions posed by the participants or their families. For those agreeing to participate, written consent was obtained from patients 18 years of age or older, or from the parent or guardian of minor patients. Assent was obtained from all patients who were minors. Standardized tests and interviews were administered at a time convenient for each participant but as close as possible to the time of hospital admission (mean [ + S D ] , 20 _+ 13 days after admission). The time of testing varied because it was necessary for some patients in the oncology group to u~adergo extensive diagnostic procedures before assignment to a treatment protocol. Measures. An interview schedule adapted from other studies20, 21 was administered to the two groups of patients. Additional interview questions were added to assess knowledge of research participation. Questions addressed the recommended elements of research participation: purpose of the research, benefit to self, benefit to others, alternative treatments, duration of the research, freedom to ask questions, freedom to withdraw from the research, procedures to be used, and risks of the research. In addition, questions were included to assess the role of the subject as a participant, the voluntary nature of participating in research, and questions about whether the subjects knew they were participants in research (vs a nonresearch therapeutic treatment regimen). We assessed 12 elements of research
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Table I. N u m b e r and percentage of the 44 obese
Table II. M e a n importance rankings (1 to 12) of
patients and patients with cancer who responded correctly to the elements of consent
elements of research participation by 11 pediatricians and assigned weight for each element
Element of consent
No.
%
Purpose of research Benefit to self Benefit to others Alternative treatments Duration of research Freedom to ask questions Freedom to withdraw Knew 50% or more procedures Knew 50% or fewer risks Role of participant Voluntary participation Knowledge of research participation
1 27 9 19 33 38 17 6 4 25 29 11
2.4 64.0 20.0 45.0 78.6 90.5 40.5 14.4 9.5 59.5 69.0 23.8
participation, rather than the recommended eight. S o m e samples of questions were as follows: " W h a t are the side effects of taking your treatment? .... How will the treatment help you? . . . . Are there other treatments for your disease besides the one you are getting now?" The interviews were conducted by a pediatric nurse practitioner. Each interview was audiotaped. Ten of the elements of research participation were coded yes, meaning that the participant had correct knowledge of that element, or no, meaning inadequate knowledge of that element. The remaining two elements were coded yes if the participant knew 50% or more of the procedures or risks stated in the protocol. A correct response was determined from information outlined in the consent/assent document of the medical protocol. The yes scores on the 12 elements were collectively referred to as the knowledge-of-participation-in-research score. Trained coders (a pediatric nurse practitioner and pediatric graduate nursing students) judged whether a response was correct. The coders were trained by a pediatric nurse practitioner with extensive experience in the pediatric oncology unit. Each element was then weighted in terms of its perceived importance because we believed that some of the 12 elements were more important for the subjects to know than were others. To determine the weight for each element, 11 pediatricians practicing in the research institution were asked to rank the importance of the 12 elements for children participating in clinical research, from 1, the most important element, to 12, the least important element. Each element then was assigned a weight based on the mean ranking of the pediatricians. The scale for the weighted score was reversed (from 12 -- most important; 1 = least important) from the rankings by the pediatricians. The
Components of research participation
Benefit to self Risks Procedures Purpose of research Duration of research Freedom to ask questions Voluntary participation Role of participant Alternative treatments Freedom to withdraw Knowledge of research participation Benefit to others
M e a n rank*
Given weightt
4.14 4.14 4.23 4.91 5.82 6.18 6.18 6.18 8.36 8.50 8.77
9 9 9 8 7 7 7 7 5 4 4
9.17
4
*A rating of 1 represented the most important element; a rating of 12 represented the least important element. "~Aweight of 9, corresponding to an importance rank of 4, was given to the most important mean rank. A weight of 4, corresponding to an importance rank of 9, was givento the least important mean rank. Mean rankings were rounded to the closest whole number.
weighted scores will be collectively referred to as the weighted knowledge-of-participation-in-research score. Coders had no knowledge of the study hypotheses. Interrater agreement for the knowledge-of-participation-in-research score on a random sample of 52% of the interviews had a kappa value of 22 0.72. Statistical analyses consisted of frequency counts, percentages, and t tests. RESULTS The results are presented as follows: (1) the frequency and percentage of the number of correct responses for each element (knowledge-of-participation-in-research score), (2) the score on each element, based on the previously described rankings by the pediatricians (weighted knowledge-of-participation-in-research score), (3) age differences in each of the two scores, and (4) consensus between participants and physicians on the importance of the elements of consent. Knowledge-of-partlcipatlon-in-research score. W e determined the frequency with which our study subjects (children, adolescents, and young adults) responded correctly to the elements of research participation, and the percentage of subjects who responded. More than half of the subjects knew the benefits to self of participating in the study, the duration of the research, that they were free to ask questions, their role as participant, and that participation was voluntary. Fewer than half knew the purpose of the research, the benefit to others, alternative treatments, that
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Table III. Physician ratings of importance of elements of consent, and percentage of study subjects responding correctly to each element Importance ranking Element of consent Purpose of the research Benefit to self Knew 50% or more procedures Knew 50% or fewer risks Duration of research Freedom to ask questions Role of participant Voluntary participation Benefit to others Alternative treatments Freedom to withdraw Knowledge of research participation
Most (%)
Middle (%)
Least (%)
2.4 64.0 14.4 9.5 78.6 90.5 59.5 69.0 20.0 45.0 40.5 23.8
they were free to withdraw, the procedures and risks of the protocol, and the elements of research participation (Table I).
Weighted knowledge-of-participation-in-research score. The mean importance ranking by pediatricians and the weighted knowledge-of-participation-in-research score for each element appears in Table II. If a subject knew all 12 elements, the maximum score was 80. The weighted scores in the total sample ranged from 16.4 to 57.9 (mean 36.8 +_ 12.3).
Age differences in knowledge-of-participatlon-in-research scores. Our study subjects were grouped into two age groups: 7 to 13 years of age (n = 15) and 14 to 21 years (n = 27). We chose age 14 years as the dividing age because the literature on child development23 and our own findings2~ suggested that most individuals older than this age are capable of abstract reasoning, an intellectual ability needed to understand many aspects of the scientific process. A t test showed no mean differences between the older and younger groups in the knowledge-of-participation-inresearch scores: t (df= 40) = -0.99; p = 0.33. Similarly, there were no mean differences in the weighted knowledgeof-participation-in-research scores: t ( d f = 4 0 ) = - 0 . 9 7 ; p = 0.34. In the younger group the weighted score ranged from 16.4 to 57.1 (mean = 34.3 + 14.4), and in the older group the scores ranged from 17.7 to 57.9 (mean = 38.1 _ 21.0). Consensus between physicians and participants. We examined the association between what physicians believe is important for children and adolescents to know about participation in research and what these patients actually
know. We divided the elements into three categories based on the importance ratings by the physicians (Table III): (1) the four most important elements, (2) the four elements of intermediate importance, and (3) the four least important elements. The elements of research participation next were divided into those on which more than half the participants answered correctly and those on which less than half the participants answered correctly. One element in the most important category, as rated by the physicians, was answered correctly by more than half the participants, four elements in the intermediate category, and no elements in the least important category. Three elements in the most important category, as rated by the physicians, were answered correctly by fewer than 50% of the participants, no elements in the intermediate category, and four elements in the least important category. These findings indicate a lack of consensus between what our participants actually knew about research participation and what physicians believe is most important for these participants to know. However, there is consensus between what these participants did not know about research participation and the knowledge that physicians believe is of moderate or least importance. DISCUSSION Our findings reflect both optimistic and less-than-optimistic findings about what children, adolescents, and young adults understand about participating in research. The elements of participation in research relating to concrete experiences in the lives of our subjects were most often answered correctly. For example, most children were aware of the time dimension or duration of their treatment. Even young children, in their everyday lives, are aware of timeoriented events (e.g., number of days preceding a holiday). Furthermore, more than 50% knew their role as participant or what was required of them during participation in the study. A d~velopmental task of childhood is learning roles appropriate to specific contexts. For example, children learn in the early school years their role as student (rules of the classroom), friend, and family member. Children also learn the concepts of volunteering and of being free to ask questions in the school setting. Teachers rely on the volunteer efforts of children to accomplish multiple educational objectives. In schools, children are encouraged to ask questions, a tendency that appeared to generalize to a medical setting. The perception of freedom to ask questions may reflect the trusting nature of the relationship between hospitalized children and the medical team. Not surprisingly, 64% of the children, adolescents, and young adults knew the benefits to themselves of participating in a research protocol. The elements of research participation relating to ab-
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stract issues were less often answered correctly. These elements included the purpose of the research, benefits to others, knowledge that one is a research participant, freedom to withdraw from the study, and alternative treatments. These elements require an understanding of abstract scientific concepts, including the concepts of randomization and investigational therapy. Comprehension of these concepts depends on the intellectual capability of abstract reasoning, an ability that emerges during early to mid adolescence. The element least often answered correctly was the purpose of the study. The "correct" response was considered the scientific purpose of the study. The majority of the study subjects mentioned the therapeutic purpose of the treatment ("to get better" or "to be cured"). These responses might also be considered correct because the explanation of a study is described mainly in terms of its therapeutic goals, with less emphasis on its scientific goals (e.g., "to determine which treatment or drug regimen is more effective in treating your disease"). The children correctly stated that the aim of a clinical study is its therapeutic goal. Patients rarely participate as volunteers in research merely a s a scientific endeavor; being cured is the primary issue that obscures all other scientific issues. The scientific purpose of a research study is an abstraction involving complicated scientific, theoretical, and methodologic issues. To understand the purpose of randomization to one of two treatments, for instance, involves some appreciation of probability theory. Patients inexperienced with scientific concepts may fail to grasp the connection between a research hypothesis and one's disease processes. Fewer than 15% of the study subjects responded correctly to questions related to knowledge of the procedures and risks of the study in which they were participating. We had assumed that the participants would be well aware of the procedures and risks involved because of the importance that physicians and nurses placed on patients' understanding of risks and procedures and because of the thorough oral and written explanation of the studies provided by the staff to both the patients and their families. For most patients, the medical procedures referred to in the consent or assent forms may be totally unfamiliar and thus difficult to recall. Failure to recall risks, as opposed to procedures, may involve different psychologic processes. Patients may deny the risks involved to justify to themselves the unpleasant aspects of their treatment. In addition, the large number of procedures or risks entailed in intensive treatment regimens may be difficult to remember for a young patient whose condition has only recently been diagnosed. We recommend that informed assent/consent procedures become an ongoing component of medical treatment. Continuing to provide information about the protocol may help to overcome potential initial information overload and to improve overall
Consent process in biomedical research
55 1
comprehension of the research and treatment. We also recommend that investigators ask patients questions to determine what they know about important elements of consent (e.g., the purpose of the study and its duration). Through the patient responses, investigators can provide more targeted information to enhance overall understanding of research participation. If informed consent were judged by the criterion of the number of children who responded correctly to the consent elements, one might be tempted to conclude that our study subjects were not well informed about the nature of their participation in research. We suggest another interpretation. We evaluated knowledge of research participation by using standards developed to provide guidelines for obtaining informed consent of adults because no guidelines are available for children. Nonetheless, the findings on the children, adolescents, and young adults in this study were not unlike the findings on adults in previous studies, who also varied in the degree to which they appeared to comprehend participation in research.l l 13 Developmental issues in children and adolescents merely compound the informed consent problems all patient-subjects face. Although we found no age differences, developmental differences do exist among children, adolescents, and adults in the ways the world is conceptualized, indicating that minors require special consideration with regard to how informed assent is obtained. Until early adolescence, children are unlikely to comprehend the meaning of abstract scientific concepts; their lack of experience and their emotional immaturity may impede competent decision making. Adolescents and young adults were no better than children in comprehending abstract concepts. Adolescents and young adults may possess the ability to use formal reasoning in some instances (i.e., mathematics), but reasoning about scientific concepts and medical procedures requires factual knowledge that most adolescents and young adults do not possess. Thus these younger patients may lack the experiential skills needed to make truly informed decisions about participation in research. Future research might focus on how younger patients differ from mature adults in their knowledge of participation in research. In our study the obese patients and those with cancer undoubtedly dealt with different psychologic issues because of the life-threatening nature of cancer. Ethical dilemmas encountered in pediatric oncology settings offer a particular challenge and have been addressed elsewhere. 24 Group differences between obese participants and those with cancer might be anticipated, and yet there were many interindividual differences among both types of patients in the correctness of their responses to the elements of consent. We suggest that regardless of the diagnosis, each patient must be addressed at his or her developmental level. An empha-
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sis on group differences based on diagnoses may detract attention from the psychologic processes involved in understanding the nature of participation in research for all children versus specific groups of children. A caveat is that our findings may not generalize to biomedical research that entails less intensive biomedical regimens. Finally, although children, adolescents, and young adults may appear to know less than we would like them to know about participation in research, our findings should not be used to discourage their inclusion in the consent/assent process in research. For some children, the experimental treatment in which they are participating is the only possibility for sustaining life. For others, the reward m a y not be therapeutic, but participating in research may sensitize them to the altruistic merits of participating in research now and throughout life. The challenge to biomedical researchers is to protect children and adolescents from undue risks from research participation because of the vulnerabilities inherent in these developmental stages, while maintaining respect for their right to gain the therapeutic and altruistic benefits of participating in research. To succeed in both domains, one should consider developmental processes and individual (versus group) differences when requesting assent to participate in biomedical research. We thank the medical and nursing staff of the patient units where the data were collected for their support of this project. We also thank the children, adolescents, and young adults who shared sensitive information about their illness and treatment. REFERENCES
1. Lewis CE, Lewis MA, Ifekwunique M. Informed consent by children and participation in an influenza vaccine trial. Am J Public Health 1978;68:1079-82. 2. Schwartz AH. Children's concepts of research hospitalization. N Engl J Med 1972;287:589-92. 3. Weithorn LA, Campbell SB. The competency of children and adolescents to make informed treatment decisions. Child Dev 1982;53:1589-98. 4. Grisso T, Vierling L. Minors' consent to treatment: a developmental perspective. Professional Psychology 1978;9:413-27. 5. Lewis CC. Minors' competence to consent to abortion. Am Psychol 1987;42:84-8. 6. Epstein LC, Lazagna L. Obtaining informed consent. Arch Intern Med 1969;123:682-8.
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7. Anderson JL. Patients' recall of information and its relation to the nature of the consultation. In: Osborne D, Gruneberg M, Eiser J, eds. Research in psychology and medicine. London: Academic Press, 1979:238-46. 8. Rimer BK, Jones WL, Keintz MK, et al. Cancer patients' recall of important information. Prog Clin Biol Res 1984; 156:153-9. 9. Morrow G, Gootnick J, Schmale A. A sample technique for increasing cancer patients' knowledge of informed consent to treatment. Cancer 1978;42:793-9. 10. Taub HA. Informed consent, memory, and age. Gerontologist 1980;20:686-90. 11. Schultz AL, Pardee GP, Ensinck JW. Are research subjects really informed? West J Med 1975;123:76-80. 12. Kennedy B J, Lillehaugen T. Patient recall of informed consent. Med Pediatr Oncol 1979;7:173-8. 13. Muss HB, White DR, Michielutte R, et al. Written informed consent in patients with breast cancer. Cancer 1979;43:154956. 14. McCollum AT, Schwartz AH. Pediatric research hospitalization: its meaning to parents. Pediatr Res 1969;3:199-204. 15. U.S. Department of Health, Education, and Welfare. Protection of human subjects: policies and procedures. Part IL Federal Register 1973 Nov 16;38:221. 16. Proposed regulations on research involving children. Federal Register 1978 July 21;43:141. 17. U.S. Department of Health and Human Services. 45 Code of Federal Regulations 46. Subpart D--Additional protection for children involved as subjects in research. Federal Register 1983 March 8;48:9818. 18. Holler AR. Minors' right to consent to medical care. JAMA 1987;257:3400-2. 19. Hollingshead AB. Four-factor index of social status. New Haven, Connecticut: Yale University Department of Sociology, 1975. 20. Susman E J, Dorn LD, Fletcher JC. Reasoning about illness in ill and healthy children and adolescents: cognitive and emotional developmental aspects. J Dev Behav Pediatr 1987;8:26673. 21. Susman E J, Hersh SP, Nannis ED, et al. Conceptions of cancer: the perspectives of child and adolescent patients and their families. J Pediatr Psyehol 1982;7:253-61. 22. Bartko J J, Carpenter WT. On the methods and theory of reliability. J Nerv Ment Dis 1976;163:307-17. 23. Piagbt J, Inhelder B. The psychology of the hhild. New York: Basic Books, 1969. 24. Fletcher JC, van Eys J, Dorn LD. Ethical considerations in pediatric oncology. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. Philadelphia: JB Lippincott, 1989:309-20.
We examined the c a p a c i t y of children, adolescents, and young adults to assent and consent to participation in biomedical research, and what physicianinvestigators believe is important for patients in these a g e groups to know about such participation. The sample included 44 male and female subjects, ranging in a g e from 7 to 20 years, who were hospitalized to treat either pediatric c a n c e r or obesity. The participants c o m p l e t e d a structured interview that assessed knowledge of research participation using the elements outlined in the federal guidelines for informed consent. The study subjects were most k n o w l e d g e a b l e about those elements of consent that assessed concrete information (e.g., freedom to ask questions, time elements involved, and the benefits of participation). They were less k n o w l e d g e a b l e about those elements of informed consent that assessed abstract information (e.g., scientific vs therapeutic purpose of the study, and alternative treatments). Chronologic a g e was not related to knowledge of the elements of informed consent. The strategies that the study subjects used to reason about participation in research a p p e a r e d to parallel their reasoning about other physical phenomena. (J PEDIATR1992;121:547-52)
Children's participation in biomedical and behavioral research presents ethical dilemmas for researchers as well as for the parents who provide legal permission for their children to participate. Only recently have studies begun to examine children's understanding of human experimentation, 1,2 their capacity to consent,3 and developmental differences in their capacity to consent to research participation.4, 5 In the situations examined, children can partic-
Supported in part (L.D.D.) by a National Research Service Award (SRC-5-F31-NR05965) from the National Center for Nursing Research, National Institutes of Health. Submitted for publication Feb. 26, 1992; accepted May 20, 1992. Reprint requests: Elizabeth J. Susman, PhD, E-314 Health and Human Development Bldg., Pennsylvania State University, University Park, PA 16802. *Now at the University of Virginia School of Medicine, Charlottesville. 9/20/39511
ipate in some aspects of the consent process. To our knowledge, no empiric studies have examined the consent process for children who participate in biomedical research. Among adults, knowledge of experimental treatment-the essence of informed consent--improved when consent forms were shorter or when less information was provided in the forms, 6-8 when the consent form was sent home before the procedure, 9 and when participants had a good vocabulary. 1~ Studies also have revealed that adult patients are not well informed about the nature of clinical research participation,11-13 and parents are not well informed about the nature of their child's participation in research. 14 This less-than-optimal knowledge about research participation exists in spite of regulations requiring that informed consent be obtained from subjects over the age of majority. In the informed consent process, the patient must be given an explanation of the nature and purpose of the research; the procedures used, including those experimental in nature; the short- and long-term risks and discomforts; and the 547
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anticipated benefit to self and others. In addition, alternative treatments and the duration of the research must be disclosed, and the patient must be given freedom to ask questions at any time and freedom to withdraw from the research. Acting on recommendations of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 15, 16 the federal government also formulated regulations about the necessity of obtaining children's assent to participate in research. 17 These regulations state that when research involves a child aged 7 years or older, legal permission must be obtained from the parent or guardian and assent must be obtained from the child. Each institutional review board has the responsibility to determine the necessity of obtaining assent from children enrolled in a protocol. The regulations also state that age, maturity, and psychologic state should be considered in the determination of whether children are capable of assenting to participation in research. We sought to examine the capacity of children, adolescents, and young adults to assent and consent to participation in research. Our aim was to generate findings that could help protect children from an inappropriate degree of inclusion or exclusion in the assent process. Because cognitive abilities increase with age, we expected that the capacity to comprehend more about research participation would be greater in older children, adolescents, and young adults than in younger children. We also examined what physician investigators believe is important for children and adolescents to know compared with what our study subjects actually knew about participation in research. METHOD Participants. Forty-four male and female subjects ranging in age from 7 to 20 years participated in the study. These ages were included because guidelines for research with human subjects suggest that children younger than age 7 years cannot assent to research, and because adolescents and young adults up to age 21 years represent the oldest age group in many pediatric settings. Legally, anyone 18 years of age or older is an adult for purposes of health care consent. 18 Children, adolescents, and young adults in our study were from skilled worker or managerial level homes as determined by the family occupational and educational levels. 19 Participants consisted of two patient groups admitted for the first time to a research institution. Approval for our study was obtained from the institutional review board where the data were collected~ . The first group of patients consisted of 11 female and 9 male subjects receiving experimental treatment for pediatric cancers (age range, 7 to 20 years; mean [+_SD] age, 14.6 + 3.9). The diagnoses were Ewing sarcoma, n = 6; Burkitt lymphoma, n = 5; rhabdomyosarcoma, n = 3; os-
The Journal of Pediatrics October 1992
teogenie sarcoma, n = 1; acute lymphocytic leukemia, n = 1; and lymphomas or soft tissue tumors, n = 4. Cancers were newly diagnosed in 17 patients, and no treatment had been given elsewhere for their disease. Eleven patients had been hospitalized previously for their current disease, but hospitalization had been primarily for diagnostic rather than for treatment purposes. For all participants, the current hospitalization was their first admission to a research hospital. The second group of patients consisted of 21 girls and 3 boys who were receiving treatment for obesity (age range, 7 to 17.3 years; mean [ +_SD] age, 13.9 ___ 2.6 years). Children and adolescents in this group were hospitalized as inpatients for 3 weeks on a unit primarily housing children with endocrine disorders and obesity. All patients weighed at least 50% more than the ideal body weight according to height-for-weight standards. The ratio of girls to boys in the sample is representative of the numbers referred for obesity treatment in the institution. Procedures. After being enrolled in a medical protocol, all eligible patients and their parents were approached by the investigators and given verbal and written explanations of this study. Questions were answered and the informed consent or assent form was given to patients who met the criteria for participation. A few days later the investigators returned to review the study and answer any questions posed by the participants or their families. For those agreeing to participate, written consent was obtained from patients 18 years of age or older, or from the parent or guardian of minor patients. Assent was obtained from all patients who were minors. Standardized tests and interviews were administered at a time convenient for each participant but as close as possible to the time of hospital admission (mean [ + S D ] , 20 _+ 13 days after admission). The time of testing varied because it was necessary for some patients in the oncology group to u~adergo extensive diagnostic procedures before assignment to a treatment protocol. Measures. An interview schedule adapted from other studies20, 21 was administered to the two groups of patients. Additional interview questions were added to assess knowledge of research participation. Questions addressed the recommended elements of research participation: purpose of the research, benefit to self, benefit to others, alternative treatments, duration of the research, freedom to ask questions, freedom to withdraw from the research, procedures to be used, and risks of the research. In addition, questions were included to assess the role of the subject as a participant, the voluntary nature of participating in research, and questions about whether the subjects knew they were participants in research (vs a nonresearch therapeutic treatment regimen). We assessed 12 elements of research
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Table I. N u m b e r and percentage of the 44 obese
Table II. M e a n importance rankings (1 to 12) of
patients and patients with cancer who responded correctly to the elements of consent
elements of research participation by 11 pediatricians and assigned weight for each element
Element of consent
No.
%
Purpose of research Benefit to self Benefit to others Alternative treatments Duration of research Freedom to ask questions Freedom to withdraw Knew 50% or more procedures Knew 50% or fewer risks Role of participant Voluntary participation Knowledge of research participation
1 27 9 19 33 38 17 6 4 25 29 11
2.4 64.0 20.0 45.0 78.6 90.5 40.5 14.4 9.5 59.5 69.0 23.8
participation, rather than the recommended eight. S o m e samples of questions were as follows: " W h a t are the side effects of taking your treatment? .... How will the treatment help you? . . . . Are there other treatments for your disease besides the one you are getting now?" The interviews were conducted by a pediatric nurse practitioner. Each interview was audiotaped. Ten of the elements of research participation were coded yes, meaning that the participant had correct knowledge of that element, or no, meaning inadequate knowledge of that element. The remaining two elements were coded yes if the participant knew 50% or more of the procedures or risks stated in the protocol. A correct response was determined from information outlined in the consent/assent document of the medical protocol. The yes scores on the 12 elements were collectively referred to as the knowledge-of-participation-in-research score. Trained coders (a pediatric nurse practitioner and pediatric graduate nursing students) judged whether a response was correct. The coders were trained by a pediatric nurse practitioner with extensive experience in the pediatric oncology unit. Each element was then weighted in terms of its perceived importance because we believed that some of the 12 elements were more important for the subjects to know than were others. To determine the weight for each element, 11 pediatricians practicing in the research institution were asked to rank the importance of the 12 elements for children participating in clinical research, from 1, the most important element, to 12, the least important element. Each element then was assigned a weight based on the mean ranking of the pediatricians. The scale for the weighted score was reversed (from 12 -- most important; 1 = least important) from the rankings by the pediatricians. The
Components of research participation
Benefit to self Risks Procedures Purpose of research Duration of research Freedom to ask questions Voluntary participation Role of participant Alternative treatments Freedom to withdraw Knowledge of research participation Benefit to others
M e a n rank*
Given weightt
4.14 4.14 4.23 4.91 5.82 6.18 6.18 6.18 8.36 8.50 8.77
9 9 9 8 7 7 7 7 5 4 4
9.17
4
*A rating of 1 represented the most important element; a rating of 12 represented the least important element. "~Aweight of 9, corresponding to an importance rank of 4, was given to the most important mean rank. A weight of 4, corresponding to an importance rank of 9, was givento the least important mean rank. Mean rankings were rounded to the closest whole number.
weighted scores will be collectively referred to as the weighted knowledge-of-participation-in-research score. Coders had no knowledge of the study hypotheses. Interrater agreement for the knowledge-of-participation-in-research score on a random sample of 52% of the interviews had a kappa value of 22 0.72. Statistical analyses consisted of frequency counts, percentages, and t tests. RESULTS The results are presented as follows: (1) the frequency and percentage of the number of correct responses for each element (knowledge-of-participation-in-research score), (2) the score on each element, based on the previously described rankings by the pediatricians (weighted knowledge-of-participation-in-research score), (3) age differences in each of the two scores, and (4) consensus between participants and physicians on the importance of the elements of consent. Knowledge-of-partlcipatlon-in-research score. W e determined the frequency with which our study subjects (children, adolescents, and young adults) responded correctly to the elements of research participation, and the percentage of subjects who responded. More than half of the subjects knew the benefits to self of participating in the study, the duration of the research, that they were free to ask questions, their role as participant, and that participation was voluntary. Fewer than half knew the purpose of the research, the benefit to others, alternative treatments, that
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Table III. Physician ratings of importance of elements of consent, and percentage of study subjects responding correctly to each element Importance ranking Element of consent Purpose of the research Benefit to self Knew 50% or more procedures Knew 50% or fewer risks Duration of research Freedom to ask questions Role of participant Voluntary participation Benefit to others Alternative treatments Freedom to withdraw Knowledge of research participation
Most (%)
Middle (%)
Least (%)
2.4 64.0 14.4 9.5 78.6 90.5 59.5 69.0 20.0 45.0 40.5 23.8
they were free to withdraw, the procedures and risks of the protocol, and the elements of research participation (Table I).
Weighted knowledge-of-participation-in-research score. The mean importance ranking by pediatricians and the weighted knowledge-of-participation-in-research score for each element appears in Table II. If a subject knew all 12 elements, the maximum score was 80. The weighted scores in the total sample ranged from 16.4 to 57.9 (mean 36.8 +_ 12.3).
Age differences in knowledge-of-participatlon-in-research scores. Our study subjects were grouped into two age groups: 7 to 13 years of age (n = 15) and 14 to 21 years (n = 27). We chose age 14 years as the dividing age because the literature on child development23 and our own findings2~ suggested that most individuals older than this age are capable of abstract reasoning, an intellectual ability needed to understand many aspects of the scientific process. A t test showed no mean differences between the older and younger groups in the knowledge-of-participation-inresearch scores: t (df= 40) = -0.99; p = 0.33. Similarly, there were no mean differences in the weighted knowledgeof-participation-in-research scores: t ( d f = 4 0 ) = - 0 . 9 7 ; p = 0.34. In the younger group the weighted score ranged from 16.4 to 57.1 (mean = 34.3 + 14.4), and in the older group the scores ranged from 17.7 to 57.9 (mean = 38.1 _ 21.0). Consensus between physicians and participants. We examined the association between what physicians believe is important for children and adolescents to know about participation in research and what these patients actually
know. We divided the elements into three categories based on the importance ratings by the physicians (Table III): (1) the four most important elements, (2) the four elements of intermediate importance, and (3) the four least important elements. The elements of research participation next were divided into those on which more than half the participants answered correctly and those on which less than half the participants answered correctly. One element in the most important category, as rated by the physicians, was answered correctly by more than half the participants, four elements in the intermediate category, and no elements in the least important category. Three elements in the most important category, as rated by the physicians, were answered correctly by fewer than 50% of the participants, no elements in the intermediate category, and four elements in the least important category. These findings indicate a lack of consensus between what our participants actually knew about research participation and what physicians believe is most important for these participants to know. However, there is consensus between what these participants did not know about research participation and the knowledge that physicians believe is of moderate or least importance. DISCUSSION Our findings reflect both optimistic and less-than-optimistic findings about what children, adolescents, and young adults understand about participating in research. The elements of participation in research relating to concrete experiences in the lives of our subjects were most often answered correctly. For example, most children were aware of the time dimension or duration of their treatment. Even young children, in their everyday lives, are aware of timeoriented events (e.g., number of days preceding a holiday). Furthermore, more than 50% knew their role as participant or what was required of them during participation in the study. A d~velopmental task of childhood is learning roles appropriate to specific contexts. For example, children learn in the early school years their role as student (rules of the classroom), friend, and family member. Children also learn the concepts of volunteering and of being free to ask questions in the school setting. Teachers rely on the volunteer efforts of children to accomplish multiple educational objectives. In schools, children are encouraged to ask questions, a tendency that appeared to generalize to a medical setting. The perception of freedom to ask questions may reflect the trusting nature of the relationship between hospitalized children and the medical team. Not surprisingly, 64% of the children, adolescents, and young adults knew the benefits to themselves of participating in a research protocol. The elements of research participation relating to ab-
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stract issues were less often answered correctly. These elements included the purpose of the research, benefits to others, knowledge that one is a research participant, freedom to withdraw from the study, and alternative treatments. These elements require an understanding of abstract scientific concepts, including the concepts of randomization and investigational therapy. Comprehension of these concepts depends on the intellectual capability of abstract reasoning, an ability that emerges during early to mid adolescence. The element least often answered correctly was the purpose of the study. The "correct" response was considered the scientific purpose of the study. The majority of the study subjects mentioned the therapeutic purpose of the treatment ("to get better" or "to be cured"). These responses might also be considered correct because the explanation of a study is described mainly in terms of its therapeutic goals, with less emphasis on its scientific goals (e.g., "to determine which treatment or drug regimen is more effective in treating your disease"). The children correctly stated that the aim of a clinical study is its therapeutic goal. Patients rarely participate as volunteers in research merely a s a scientific endeavor; being cured is the primary issue that obscures all other scientific issues. The scientific purpose of a research study is an abstraction involving complicated scientific, theoretical, and methodologic issues. To understand the purpose of randomization to one of two treatments, for instance, involves some appreciation of probability theory. Patients inexperienced with scientific concepts may fail to grasp the connection between a research hypothesis and one's disease processes. Fewer than 15% of the study subjects responded correctly to questions related to knowledge of the procedures and risks of the study in which they were participating. We had assumed that the participants would be well aware of the procedures and risks involved because of the importance that physicians and nurses placed on patients' understanding of risks and procedures and because of the thorough oral and written explanation of the studies provided by the staff to both the patients and their families. For most patients, the medical procedures referred to in the consent or assent forms may be totally unfamiliar and thus difficult to recall. Failure to recall risks, as opposed to procedures, may involve different psychologic processes. Patients may deny the risks involved to justify to themselves the unpleasant aspects of their treatment. In addition, the large number of procedures or risks entailed in intensive treatment regimens may be difficult to remember for a young patient whose condition has only recently been diagnosed. We recommend that informed assent/consent procedures become an ongoing component of medical treatment. Continuing to provide information about the protocol may help to overcome potential initial information overload and to improve overall
Consent process in biomedical research
55 1
comprehension of the research and treatment. We also recommend that investigators ask patients questions to determine what they know about important elements of consent (e.g., the purpose of the study and its duration). Through the patient responses, investigators can provide more targeted information to enhance overall understanding of research participation. If informed consent were judged by the criterion of the number of children who responded correctly to the consent elements, one might be tempted to conclude that our study subjects were not well informed about the nature of their participation in research. We suggest another interpretation. We evaluated knowledge of research participation by using standards developed to provide guidelines for obtaining informed consent of adults because no guidelines are available for children. Nonetheless, the findings on the children, adolescents, and young adults in this study were not unlike the findings on adults in previous studies, who also varied in the degree to which they appeared to comprehend participation in research.l l 13 Developmental issues in children and adolescents merely compound the informed consent problems all patient-subjects face. Although we found no age differences, developmental differences do exist among children, adolescents, and adults in the ways the world is conceptualized, indicating that minors require special consideration with regard to how informed assent is obtained. Until early adolescence, children are unlikely to comprehend the meaning of abstract scientific concepts; their lack of experience and their emotional immaturity may impede competent decision making. Adolescents and young adults were no better than children in comprehending abstract concepts. Adolescents and young adults may possess the ability to use formal reasoning in some instances (i.e., mathematics), but reasoning about scientific concepts and medical procedures requires factual knowledge that most adolescents and young adults do not possess. Thus these younger patients may lack the experiential skills needed to make truly informed decisions about participation in research. Future research might focus on how younger patients differ from mature adults in their knowledge of participation in research. In our study the obese patients and those with cancer undoubtedly dealt with different psychologic issues because of the life-threatening nature of cancer. Ethical dilemmas encountered in pediatric oncology settings offer a particular challenge and have been addressed elsewhere. 24 Group differences between obese participants and those with cancer might be anticipated, and yet there were many interindividual differences among both types of patients in the correctness of their responses to the elements of consent. We suggest that regardless of the diagnosis, each patient must be addressed at his or her developmental level. An empha-
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sis on group differences based on diagnoses may detract attention from the psychologic processes involved in understanding the nature of participation in research for all children versus specific groups of children. A caveat is that our findings may not generalize to biomedical research that entails less intensive biomedical regimens. Finally, although children, adolescents, and young adults may appear to know less than we would like them to know about participation in research, our findings should not be used to discourage their inclusion in the consent/assent process in research. For some children, the experimental treatment in which they are participating is the only possibility for sustaining life. For others, the reward m a y not be therapeutic, but participating in research may sensitize them to the altruistic merits of participating in research now and throughout life. The challenge to biomedical researchers is to protect children and adolescents from undue risks from research participation because of the vulnerabilities inherent in these developmental stages, while maintaining respect for their right to gain the therapeutic and altruistic benefits of participating in research. To succeed in both domains, one should consider developmental processes and individual (versus group) differences when requesting assent to participate in biomedical research. We thank the medical and nursing staff of the patient units where the data were collected for their support of this project. We also thank the children, adolescents, and young adults who shared sensitive information about their illness and treatment. REFERENCES
1. Lewis CE, Lewis MA, Ifekwunique M. Informed consent by children and participation in an influenza vaccine trial. Am J Public Health 1978;68:1079-82. 2. Schwartz AH. Children's concepts of research hospitalization. N Engl J Med 1972;287:589-92. 3. Weithorn LA, Campbell SB. The competency of children and adolescents to make informed treatment decisions. Child Dev 1982;53:1589-98. 4. Grisso T, Vierling L. Minors' consent to treatment: a developmental perspective. Professional Psychology 1978;9:413-27. 5. Lewis CC. Minors' competence to consent to abortion. Am Psychol 1987;42:84-8. 6. Epstein LC, Lazagna L. Obtaining informed consent. Arch Intern Med 1969;123:682-8.
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7. Anderson JL. Patients' recall of information and its relation to the nature of the consultation. In: Osborne D, Gruneberg M, Eiser J, eds. Research in psychology and medicine. London: Academic Press, 1979:238-46. 8. Rimer BK, Jones WL, Keintz MK, et al. Cancer patients' recall of important information. Prog Clin Biol Res 1984; 156:153-9. 9. Morrow G, Gootnick J, Schmale A. A sample technique for increasing cancer patients' knowledge of informed consent to treatment. Cancer 1978;42:793-9. 10. Taub HA. Informed consent, memory, and age. Gerontologist 1980;20:686-90. 11. Schultz AL, Pardee GP, Ensinck JW. Are research subjects really informed? West J Med 1975;123:76-80. 12. Kennedy B J, Lillehaugen T. Patient recall of informed consent. Med Pediatr Oncol 1979;7:173-8. 13. Muss HB, White DR, Michielutte R, et al. Written informed consent in patients with breast cancer. Cancer 1979;43:154956. 14. McCollum AT, Schwartz AH. Pediatric research hospitalization: its meaning to parents. Pediatr Res 1969;3:199-204. 15. U.S. Department of Health, Education, and Welfare. Protection of human subjects: policies and procedures. Part IL Federal Register 1973 Nov 16;38:221. 16. Proposed regulations on research involving children. Federal Register 1978 July 21;43:141. 17. U.S. Department of Health and Human Services. 45 Code of Federal Regulations 46. Subpart D--Additional protection for children involved as subjects in research. Federal Register 1983 March 8;48:9818. 18. Holler AR. Minors' right to consent to medical care. JAMA 1987;257:3400-2. 19. Hollingshead AB. Four-factor index of social status. New Haven, Connecticut: Yale University Department of Sociology, 1975. 20. Susman E J, Dorn LD, Fletcher JC. Reasoning about illness in ill and healthy children and adolescents: cognitive and emotional developmental aspects. J Dev Behav Pediatr 1987;8:26673. 21. Susman E J, Hersh SP, Nannis ED, et al. Conceptions of cancer: the perspectives of child and adolescent patients and their families. J Pediatr Psyehol 1982;7:253-61. 22. Bartko J J, Carpenter WT. On the methods and theory of reliability. J Nerv Ment Dis 1976;163:307-17. 23. Piagbt J, Inhelder B. The psychology of the hhild. New York: Basic Books, 1969. 24. Fletcher JC, van Eys J, Dorn LD. Ethical considerations in pediatric oncology. In: Pizzo PA, Poplack DG, eds. Principles and practice of pediatric oncology. Philadelphia: JB Lippincott, 1989:309-20.
