Kodish E, Eder M, Noll RB, Ruccione K, Lange B, Angiolillo A, Pentz R, Zyzanski S, Siminoff LA, Drotar D. Communication of Randomization in Childhood Leukemia Trials. JAMA. 2004;291(4):470-475. doi:10.1001/jama.291.4.470
Author Affiliations: Rainbow Center for Pediatric Ethics, Department of Pediatrics, Rainbow Babies and Children's Hospital, University Hospitals of Cleveland (Drs Kodish and Drotar, and Ms Eder), and Departments of Pediatrics (Drs Kodish and Drotar), Family Medicine (Dr Zyzanski), and Bioethics (Dr Siminoff), Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pediatrics, Children's Hospital Medical Center, Cincinnati, Ohio (Dr Noll); Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, Calif (Ms Ruccione); Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa (Dr Lange); Department of Pediatrics, Children's National Medical Center, Washington, DC (Dr Angiolillo); and Winship Cancer Institute, Atlanta, Ga (Dr Pentz).
The Patient-Physician Relationship Section Editor: Richard M. Glass, MD, Deputy Editor.
Context Most children diagnosed as having leukemia become research subjects
in randomized clinical trials (RCTs), but little is known about how randomization
is explained to or understood by parents.
Objective To investigate physicians' explanation and parental understanding of
randomization in childhood leukemia RCTs.
Design and Setting A multisite study of the informed consent communication process for
RCTs of childhood leukemia. Consecutive cases were recruited from pediatric
oncology inpatient wards at 6 US children's hospitals associated with major
academic medical centers from July 1, 1999, until December 31, 2001. The informed
consent conferences were observed and audiotaped, and the information obtained
was coded and analyzed. Parents were interviewed shortly after the conference
to ascertain their understanding.
Participants Parents and members of the health care team who participated in 137
informed consent conferences for children with newly diagnosed acute leukemia.
Main Outcome Measures Observed explanations of randomization and parental understanding of
randomization after the consent conference.
Results Randomization was explained by physicians in 83% of cases and a consent
document was presented during the conference in 95% of cases. Interviews after
the conference demonstrated that 68 (50%) of 137 parents did not understand
randomization. Parents of racial minority and lower socioeconomic status were
less likely to understand randomization (P<.001
for each). Discussion of specific clinical trial details and the presence
of a nurse during the conference were associated with understanding. Eighty-four
percent of children were enrolled in a leukemia trial.
Conclusions Despite oral and written explanation, half of the parents in this study
did not understand randomization for childhood leukemia trials. To make informed
consent more effective, future research must seek to improve communication
during this critical interchange.
Clinical trials provide the foundation of evidence-based medicine, and
randomization is the paramount principle of trial design.1,2 Despite
theoretical concerns about the ethics of randomized trials,3- 7 empirical
knowledge is lacking. Thousands of children with cancer have been enrolled
in randomized clinical trials (RCTs) during the past 40 years.8 The
cure of childhood leukemia, one of the great success stories of modern medicine,
has been a direct result of these trials.9 For
children with newly diagnosed leukemia and their families, randomization is
the key feature that distinguishes research participation from treatment outside
an RCT. Placebos are not used in childhood leukemia RCTs.
Federal regulations require that parents of a child recently diagnosed
as having leukemia provide informed consent for research participation before
that child's treatment is randomly allocated to one of multiple treatment
groups of the RCT.10 Parental understanding
of the process of randomization is therefore necessary but not sufficient
for truly informed consent.
One key question is whether the informed consent process results in
understanding of randomization. Some studies11- 13 have
shown that understanding randomization is limited among research participants.
Other studies14 have analyzed the explanation
of randomization during the informed consent process without attempting to
measure participants' understanding of the concept.
To investigate physicians' explanation and parental understanding of
randomization in this context, we conducted the Project on Informed Consent
(PIC). We hoped to answer the question, "Do parents understand that their
child's treatment will be randomly allocated?" Unlike previous studies,15,16 this research included both audiotaping
of the informed consent conference (ICC) and interviews with parents after
the conference. Accordingly, it provides a unique contribution to knowledge
in communication and research ethics by examining what physicians said in
relationship to what parents understood.
Before starting the PIC study, research associates were trained to ensure
uniformity in methods across sites. We then recruited consecutive cases at
6 institutions from July 1, 1999, until December 31, 2001. We obtained the
informed consent of the parents, physicians, and patients (when appropriate)
shortly after each patient's diagnosis of either acute lymphoblastic leukemia
(ALL) or acute myeloid leukemia (AML).
The research was performed at the Children's Hospital of Philadelphia,
Philadelphia, Pa; Children's Hospital Los Angeles, Los Angeles, Calif; Rainbow
Babies and Children's Hospital, Cleveland, Ohio; Children's Hospital National
Medical Center, Washington, DC; Children's Hospital Medical Center, Cincinnati,
Ohio; and MD Anderson Cancer Center, Houston, Tex. The appropriate institutional
review board approved the study at each site.
Research associates were present to observe and audiotape the ICCs that
physicians convened to discuss RCT participation. Research associates only
observed and did not participate in the conference. Each taped ICC was then
coded by using the Observer Checklist,17 an
instrument developed to examine behaviors specific to clinical discussions
related to cancer, and subsequently transcribed for qualitative analysis.
For quantitative analyses, we used SPSS statistical software version 11.0
(SPSS Inc, Chicago, Ill) and the level of statistical significance was set
Parents were interviewed within 48 hours of the conference. To avoid
conflicting responses from multiple family members, we limited interviews
to the parent or surrogate who was the most active participant during the
conference whenever possible.
Observer Checklist. All Observer Checklist
items were coded independently by the site research associate, one of the
authors (M.E.), and the project director, and reconciled according to a rule
book designed to limit misinterpretation of each coded item. Explanation and
understanding of randomization were defined as the main outcome measures for
this analysis. To be coded as "explains the concept of randomization," our
coding rules required that "the clinician explains what randomization means."
Any explanation of how treatment is selected for participants in the RCT qualified
for this code. For items reported in this article, the mean κ score
for intercoder reliability was 0.70 (range, 0.54-0.95), which is considered
to be good agreement among coders.18
Parent Interview. The parent interview was
designed, based on preliminary research,19 to
ascertain parental understanding. The interview was pilot tested in an iterative
sequence to confirm its accuracy in measuring parental comprehension. All
parent interview instruments were professionally translated and back-translated
to Spanish and were available for use at the discretion of the parent participants.
Interpreters were used for parent interviews when necessary.
Understanding of randomization was determined by an author (M.E.) by
using the following protocol. A combination of 2 interview questions that
assess understanding of randomization directly was evaluated first. These
questions were as follows: "In this clinical research study, how will it be
decided which treatment your child will receive?" and "If your child enrolled
in this clinical research study, will you be able to choose the treatment
option you want?"
If responses to these 2 items did not indicate parental understanding,
we proceeded to a global search of the parent's answers to all interview items
for evidence of understanding. We considered parents to understand randomization
if at any point during the interview they were able to articulate that their
child would be assigned by chance to 1 of multiple treatment groups if they
chose to enroll in the clinical trial. The Observer Checklist and parent interview
instruments are available at http://www.rainbowbabies.org/professionals/ethics.asp.
Demographics. We collected demographic information
that included patient age and sex and parent age, sex, education, occupation,
and race. We used data on occupation and education level to calculate the
Hollingshead Index of Social Position (ISP),20 which
assigns socioeconomic status (SES), for each case. On this scale of 1 to 5,
a lower ISP score represents a higher SES.20
The results are organized to provide information on demographic and
conference characteristics, general communication about the clinical trial,
and communication specific to randomization.
We approached 164 parents to request consent for the PIC study and 140
parents (85%) agreed to participate. Because clinical factors precluded eligibility
for randomization in 3 cases, the analyses reported herein were performed
on a sample of 137 parent participants.
The diagnoses of the children included 122 with ALL and 15 with AML.
These children, 78 boys and 59 girls, had a mean age of 7 years (range, 1-18
years). The parents, 83 women and 54 men, had a mean age of 35 years (range,
18-51 years). A total of 44% of the parents were of racial minority, primarily
of Latino origin. The conferences were conducted in English in 111 cases.
Twenty-four non-English cases included interpreters and 2 were conducted completely
in Spanish. We tracked the 24 cases in which parents declined the PIC study
and found no difference in the rate of participation in the leukemia RCT between
those 24 cases compared with the 137 cases reported herein.
The mean length of conferences was 79 minutes (range, 25-183 minutes),
with 7 participants per conference (range, 2-15). The Children's Cancer Group
(CCG) clinical trials presented included CCG-2961 (AML, n = 15), CCG-1952
(standard-risk ALL, n = 24), CCG-1991 (standard-risk ALL, n = 33), and CCG-1961
(high-risk ALL, n = 65). We observed presentation of the consent document
during the conference in 95% of cases. This occurred at the end of the conference
in 51% of these cases. An attending physician led the conference in 68% of
cases and a fellow led the conference in 32%. A nurse was present in 47% of
cases but nurses never led the conference or explained randomization during
the observed ICC. One hundred fifteen (84%) of 137 parents ultimately provided
consent for the leukemia RCT.
Discussion of direct benefit to the child from the clinical trial was
observed in 53% of cases and reference to altruism occurred in 75% of cases.
Treatment options outside the trial were discussed in 89% of conferences and
an explanation of how the trial differs from standard therapy was observed
in 91% of cases. Physicians explained the consent document content in 73%
of cases, drew a diagram to explain the trial in 25%, and offered to answer
questions about the study in 59% of ICCs. Physicians described the trial as
voluntary in 97% of cases but 18% of parents did not understand that they
were free to refuse study enrollment. Nineteen percent of parents reported
feeling pressure to enroll in the RCT. The right to withdraw was discussed
in 72% of cases but 20% of parents did not know that their child could withdraw
from the trial at any time.
We observed an explanation of randomization in 83% of cases. Sixty-eight
(50%) of 137 parents we interviewed did not understand randomization. Conferences
with an observed explanation of randomization were not associated with an
increased proportion of parents who understood (P =
.47). Parents who did not understand randomization were more likely to consent
to the RCT than parents who did understand randomization, although this finding
did not reach statistical significance (P = .07).
Factors associated with parental understanding of randomization are shown
in Table 1.
There were no significant differences in observed explanation of randomization
during the conference for parents of racial minority and lower SES compared
with racial majority and parents with higher SES. However, racial minority
and parents with lower SES were less likely to understand randomization (Table 2). Racial minority parents understood
randomization in only 27% of cases compared with 69% of majority parents.
Eighty-five percent of parents with an ISP score of 1 or 2 understood randomization
compared with only 39% of parents with an ISP score of 3, 4, or 5. Educational
level alone demonstrated a significant linear association (P<.001) with understanding of randomization, ranging from 7% understanding
for those with less than a high school education to 78% for those parents
who were college graduates. In a logistic regression analysis, racial differences
remained significant when controlling for SES; conversely, SES also remained
significant when controlling for racial differences. By contrast, we found
no significant parental sex differences in understanding of randomization.
Conference characteristics that were associated with parental understanding
of randomization included explanation of the different groups of the trial,
how the trial differed from standard treatment, the right to withdraw from
the RCT, and the fact that 1 group of the RCT is standard treatment (Table 1). Additionally, parents who reported
reading the consent document for the RCT were more likely to understand randomization.
Physician factors, including years of experience, training status (fellow
vs attending physician), and sex, were not associated with differences in
parental understanding, but the presence of a nurse at the ICC was associated
with understanding of randomization. The mean conference duration in cases
demonstrating parental understanding was 83 minutes compared with 74 minutes
in cases without parental understanding.
We conducted a qualitative examination of the specific ways in which
physicians explained randomization to parents. A total of 17% of the ICCs
did not include any explanation of randomization. In some of these ICCs, there
was no discussion of randomization at all; in others, the physician gave an
explanation of randomization that did not meet our coding requirements. For
example, one physician's explanation was limited to "We're not in control
The various descriptions of randomization that were used by physicians
in our sample of 137 cases were grouped into 3 categories. Many physicians
(31% of ICCs) included descriptions from more than 1 category in their explanation
of randomization. Fifty-eight percent of ICCs included reference to a computer,
45% included the use of 1 or more metaphors, and 16% included reference to
a "center" or "office" where the randomization would take place. Seven examples
that typify the various explanations of randomization are given in Box 1. The 2 metaphors most commonly used to explain randomization
were "coin toss" (48 ICCs [35%]) and "chance" (15 ICCs [11%]).
Computer (n = 80 [58%])
Examples: "The computer will assign him a regimen
and they will pick it instead of me. 'Cause I don't know which one of these
things is the best."
"And then she would get randomized by a computer to be on one of those
four arms . . . And we don't decide. It's the computer who decides."
Metaphor (n = 61 [45%])
Examples: "It's pretty much luck of the draw.
They don't look at her and say, ‘Well, she's got XYZ so she should get
Regimen C.' That's not what they do, OK? They pretty much put her name in
a hat and they draw out a number."
"And so the way that patients get assigned to the various arms or the
various choices in a protocol is by a procedure that's called randomization.
That is, it's like flipping a coin."
"It's something that will be done randomly so she has a 1 in 4 chance
of any of those arms."
Center or Office (n = 22 [16%])
Examples: "If you guys do choose to enroll
her, it's going to be something that's randomized. They're going to pick it
out in some center away from here and determine which of these arms she would
"At the end of this one, they will randomize them. And it's through
the main office that decides where each patient will go."
*ICCs indicate informed consent conferences.
We examined each of the description categories to determine which were
associated with parental understanding of randomization. There were no significant
differences in parental understanding when the various description categories
A fundamental principle of communication science is that there are frequently
discrepancies between what is said and what is heard.21 Our
findings demonstrate that common strategies to explain randomization are not
effective. Although physicians explained randomization in 83% of cases, we
found that 50% of parents did not comprehend this key aspect of their decision.
Most children (84%) were enrolled in the RCT despite this lack of understanding
and parents who did not understand randomization were slightly more likely
to consent to a leukemia trial.
The fact that optimal informed consent was not obtained does not make
these studies unethical.22- 24 Therapeutic
misconception has been shown to be prevalent in clinical research,25- 28 and
our results suggest that it may be important in the context of childhood cancer.
In these RCTs, parents may expect their child to be randomized to the best
treatment based on the child's clinical characteristics. These findings highlight
the need to improve the quality of informed consent.29
Concern about consent problems specific to racial minority and lower
SES subgroups30 prompted us to conduct analyses
of cases involving these families. We found that barriers to understanding
were especially pronounced among these parents. Although explanation of randomization
observed during the conference was consistent regardless of race and SES,
a higher proportion of parents of racial minority and lower SES did not understand
randomization. These findings suggest the need for tailored interventions
to improve communication for these families. Such interventions may be directed
toward physicians, parents, or both sets of participants in the ICC. Because
question asking is an effective way for parents to elicit information about
the trial during the consent conference,31 strategies
to encourage a more interactive consent process may be helpful. Many of the
parents in our study who did not understand randomization were of Latino ethnicity.
In this population, sensitivity to cultural issues will be critical in developing
improved communication. For example, the concept of respeto (respect for authority) may be so powerful in some Latino cultures
as to discourage question asking.32 Culturally
sensitive interventions designed to promote interaction during informed consent
might empower parents and facilitate higher levels of understanding. Training
in communication skills could assist physicians with this important and challenging
Our results suggest several ways to improve communication of randomization
(Box 2). Cases in which the
physician went beyond a basic explanation to discuss details of the RCT were
associated with a higher proportion of parental understanding. These details
included a description of the different groups of the RCT, the differences
between standard treatment and treatment in the RCT, and an explanation that
standard treatment is one of the groups of the RCT. Additionally, discussion
of the right to withdraw from the RCT at any time was associated with a higher
proportion of parental understanding. These findings indicate that presentation
of this cluster of explanations can enhance parental understanding.
Encourage parental participation in ICC, including question asking.
Describe different groups of the RCT, including the standard group.
Explain differences between treatment in RCT and off-study therapy.
Discuss the right to withdraw from the RCT.
Stress importance of reading consent document and give parents time to do so.
Seek formal communication training, including cultural sensitivity training.
Promote nurse attendance at ICCs.
Give parents and patient as much time as possible to make decision about RCT.
Provide parents with improved emotional support.
Assess parental understanding of randomization.
Provide further explanation of randomization until understanding is
*ICC indicates informed consent conference; RCT, randomized clinical
The presence of a nurse at the conference was strongly associated with
parental understanding. This may reflect the benefits of better emotional
support for parents at this difficult time, creating an environment in which
parents feel empowered to speak up, ask questions, and seek clarification.33 Although we did not observe nurses engaging in the
explanation of randomization, it is possible that their presence at the ICC
forged a relationship that allowed for later, effective explanation of randomization
before the parent interview. Future efforts to improve communication should
investigate the role of the nurse and seek to capitalize on this finding.
Parents who read the consent document were more likely to understand
randomization. There are many reasons why reading the document could affect
understanding. Many parents may read or reread the document after they have
had time to absorb the shock and trauma of their child's diagnosis and are
thus in a better state to comprehend the information about randomization.
In addition, parents may understand information better when they see it in
writing or after receiving information a second time.34 Encouraging
parents to read the consent document carefully or reviewing it with them during
the ICC may be effective ways to enhance parental understanding.
Our quantitative and qualitative analyses showed no relationship between
the explanation of randomization and parental understanding. This finding
may be partially explained by the fact that parents can come to understand
randomization in ways other than explanation by the physician. Some parents
may come into the ICC with prior understanding of randomization through past
experience with RCTs. Others may learn the meaning of randomization by reading
the consent document or talking with other health care providers such as nurses.
Effective communication depends on interaction between the provider
of information and the recipient. Physicians must always determine whether
their efforts at informed consent achieve the desired outcome of parental
understanding. After discussing an RCT, physicians should assess understanding
of randomization and clarify its meaning for those who do not yet understand.35
Several limitations of this study must be recognized. First, some consent
discussions with parents may not have been observed and taped. Once a new
case was identified, the trained researchers were diligent in their effort
to observe and record all discussions, with 23% of cases involving more than
1 meeting. Second, the fact that we observed informed consent may have affected
the consent process. Observation did not, however, affect leukemia RCT participation
rates and if physician performance was improved by the presence of an observer,
the resulting lack of parental understanding is of even more concern. Third,
the study was conducted at major academic children's hospitals in urban settings
that may not reflect practice at all hospitals. Finally, the emotional shock
that parents experience at the time of their child's leukemia diagnosis may
limit the generalizability of our findings.36,37 Studies
that examine the consent process in other contexts can address this question.
Clinical research is the key to medical progress but it must be conducted
in accordance with the highest ethical standards.24 Although
clinical research fulfills the duty to experiment, there is an equally compelling
ethical obligation to continually improve the quality of informed consent.38 Future research must identify the source of the gap
between explanation and understanding, with special attention to barriers
noted in parents of racial minority and lower SES. With the current lack of
training and increasing attention to research ethics,39 the
time is right for intervention studies aimed at improving communication.38 Lessons learned from such efforts may apply to communication
research in a wide variety of clinical settings. Although formidable challenges
remain, we hope that the results of this study will stimulate work toward
improving informed consent.