1. Johns Hopkins University - Berman Institute of Bioethics
Experiences of Children Enrolled in Pediatric Oncology Research: Implications for Assent
Yoram Unguru, MD, MS, MA
The Herman & Walter Samuelson Children’s Hospital at Sinai Division of Pediatric Hematology/Oncology
Johns Hopkins University - Berman Institute of Bioethics
Good afternoon. Before I get started, I want to thank the Root family for inviting me to speak at today’s Eli Root Memorial Lectureship Series - it is a real honor. In addition to Dr. Root’s wife, Mrs. Jane Root, I want to acknowledge his son, Ted Root, and especially Dr. Root’s grandson, TJ, who made the trip from Baltimore and are in attendance today. Over the past 15 months, I have had the pleasure of getting to know TJ. It is remarkable young people like TJ who will be the focus of my talk this afternoon.
I understand that many of you care for adults and not children; I’d like to get a show of hands: how many of you care for adults? How many care for children? And, how many of you sit on IRBs? While I realize that the adult practitioners outnumber pediatric providers, much of what I will say today is relevant to the adult world. While I care for children whose decision-making capacity is developing, I am certain that some of you care for adults who have dwindling or diminished capacity and are confronted with similar challenges and experiences as I am. Finally, for those of you engaged in research with so-called vulnerable populations, be it as an investigator or as an IRB member, I hope that what you hear today will be of benefit.
My presentation consists of two parts, the first is more conceptual and is where I offer some background about assent. I’ll briefly discuss the historical origins of assent, primarily focusing on three documents, the Belmont Report, the 1995 AAP’s Committee on Bioethics statement on assent, and federal regulations regulating research.
As you can see from the title page, I work with children who have cancer. I believe that assent and pediatric oncology share a unique link with one another. This relationship is an important one and is a useful framework for helping to appreciate assent in general. So, while much of what I have to say about assent is framed within the pediatric oncology setting, it still is relevant to assent in general.
In the second part of my talk I’ll focus on a pilot study that I’ve just recently completed, examining what children with cancer who are enrolled in pediatric oncology research protocols understand about research in general, their research-related treatment specifically, and their preferences for inclusion in decision-making.

2. DISCLOSURES
None

3. "The good parent does not just nurture to a point of maturation: he is expected to inhibit self-destructive impulses; he is expected to substitute his superior judgment for the short vision of the child; he is expected to use education, persuasion, seduction, and even force and coercion when necessary in the service of producing a healthy and independent adult."
Gaylin W. Competence: No longer all or none.  In: Gaylin W and Macklin R eds. Who speaks for the Child: The problems of proxy consent. New York: Plenum Press; 1982, 31.
I’d like to get started with a quotation which I believe sets the tone for my discussion this afternoon. As a parent I couldn’t agree more with the sentiment so articulately stated by Dr. Williard Gaylin, and I imagine that many of you who are parents feel similarly. Dr. Gaylin, a psychiatrist at Columbia, is a co-founder of The Hastings Center. In addition to being the first bioethics center of its kind in the United States, The Hastings Center is one of the premier bioethics institute in the country, tackling a wide array of issues such as clinical and research ethics, empirical and conceptual ethics, and of course health policy.
Gaylin’s comment, made nearly 30 years ago, came at a time when the medical establishment was in the midst of increasingly looking itself in the mirror, especially with regard to paternalism. More and more clinicians began to recognize what patients, medical scholars, and patient advocate groups had been saying for some time, that it was time to do away with the traditional notion of paternalism. However, Gaylin advocated that paternalism persist in one particular area – in the relationship between a parent and child, which led him to state … read quote
Let me re-iterate, I don’t disagree with Gaylin’s insight, rather I think it’s important to recognize that the day-to-day child-parent relationship, may require an adjustment of sorts in the research setting at least insofar as paternalism is concerned. It’s my hope that by the end of my talk, I will have given you reason to consider another perspective, that of the child.

4. BACKGROUND Research is a cornerstone of modern medicine
Research agenda is the sine qua non of pediatric cancer
Cancer clinical research trials
Children >>>>> Adults
Bullet #1 – Over the past forty years, five-year survival rates for children with cancer have increased from 28% to the current mark of nearly 80%. This increase is largely due to advances made in understanding disease processes and improved therapies directly linked to widespread participation by children in pediatric oncology clinical trials.
It’s fair to say that clinical research has become the sine qua non of pediatric cancer and that clinical research trials are the backbone of this endeavor. In fact, nearly 70% of children with cancer are treated according to a clinical research trial at some point during the course of their illness. Just to put this into perspective, as many of you likely are aware, in the adult cancer world, fewer than 2% of patients are enrolled in clinical trials. As reported in a recent editorial by Curt and Chabner in The Oncologist , excluding pediatric studies, more than 20% of studies at four NCI-designated Comprehensive Cancer Centers failed to recruit a single subject, while almost 60% of studies opened for 5 years had enrolled fewer than 5 patients at each site.
The impressive track record of pediatric clinical research trials in addition to the recent leveling off in survival rates has galvanized the childhood cancer community to pursue human subjects research with an even greater urgency in an effort to save more lives. As one of my colleagues, Eric Kodish says, in pediatric oncology, research defines the standard of care, the result of this fact is that most (if not all) pediatric oncologists consider clinical research trials as the gold standard and when they’re confronted with offering a treatment recommendation for a patient, their default is to offer a research protocol.

5. BACKGROUND Pediatric clinical trials are complex *
Therapeutic misconception
Bullet #1 – Inroads in understanding disease find their way from bench to the bedside in the form of increasingly complex clinical trials. A case in point is the current protocol for standard risk acute lymphoblastic leukemia, the most common of all childhood cancers. The protocol is 177 pages long and the consent forms alone are 58 pages long. To get a feel for just how complicated these trials are I’ve brought a copy of the experimental design. Don’t feel bad if you’re having a hard time figuring this out; let me reassure you that even pediatric oncologists, who do this for a living, have to mull over this for a while to make heads or tails out of it.
Bullet #2 – Numerous studies have shown how both adult research-subjects and physicians often fail to appreciate that the overarching objective of research is not the same as that of clinical care, what is known as the therapeutic misconception. [The therapeutic misconception is an important concept and is related to my study. I’ll mention it again in a few minutes, but I just want to introduce it know.]

6. WHY IS ASSENT AN IMPORTANT TOPIC?
Birth of assent
History of assent
National Commission + Belmont Report
American Academy of Pediatrics
So, why is assent an important area of ethics related research? Well, as I mentioned, the pediatric cancer community (rightfully so) strongly believes in the benefits of research and is determined to promote this belief by enrolling as many children with cancer in research studies. Now, if both adult research subjects and physicians fall prey to the therapeutic misconception, it’s fair to assume, and as my clinical experience supports, children do too. As a physician-investigator (who enrolls children on research protocols), my colleagues and I owe it to the children we take care of to make sure that they comprehend and appreciate what it means to be a research subject.
Before my days in medicine I studied history, so if you’ll indulge me I’d like to change hats and briefly talk about assent’s historical origins.

7. BELMONT
“Because the subject's ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject's capacities.”
“Investigators are responsible for ascertaining that the subject has comprehended the information.”
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979). The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, DC: US Government Printing Office.
Three years ago marked the thirtieth birthday of the assent requirement, which can be traced back to the National Commission’s 1977 report [on the Protection of Human Subjects of Biomedical and Behavioral Research]. It’s actually the Belmont Report, published two years later, that lends the most support for my claim for the importance of determining research subjects’ (children’s) understanding and this was reiterated by the AAP’s statement on assent in The Belmont Report continues to serve as the reference for ethically sound human subjects research. Without exception, all physicians and investigators who conduct research with children, as well as every IRB that oversees research, is required to be familiar with the Belmont Report, as any of you have submitted to the old investigator 101 and CITI training modules can attest.
For those who haven’t had a chance, take a few seconds to read these two excerpts from the Report. As you can see, Belmont places investigator’s as responsible for making sure that the information they present is understandable and that they ascertain that research subjects have comprehended information about the research they participate in. Yet there is a disconnect between this recommendation and federal regulations, which do not require that investigators assess research subjects’ understanding of information. I believe that this is a serious omission; one that has the potential for preventing assent from being meaningful.
Now some of you may correctly point out that Belmont talks about “research subjects” and not about children. However, on the page 7 of the Report, immediately following the 2 excerpts in this slide, the Report says two things that are often overlooked. The first statement is that it may be appropriate to administer a test to verify subjects’ comprehension. The second statement relates specifically to children and is as follows, “Special provision may need to be made when comprehension is severely limited, for example, by conditions of immaturity, e.g., children.” The Report takes this one step further when it says, “Each class of subjects should be considered on its own terms.” So the claim that Belmont doesn’t discuss children isn’t accurate.

8. AAP
“[Make] a clinical assessment of [the] patient’s understanding of the situation and the factors influencing how he or she is responding, including whether there is inappropriate pressure to accept testing or therapy.”
Committee on Bioethics, American Academy of Pediatrics. Informed consent, parental permission, and assent in pediatric practice. Pediatrics 1995;95:
Before Bullet #1 - While Belmont relates to research, the AAP’s statement focuses on clinical practice, this is an important distinction. However, because many children, especially those in pediatric oncology, are enrolled in therapeutic or clinical research protocols, what the AAP says is pertinent. For those not familiar with the AAP statement, it’s worthwhile to hear what it has to say. Namely, that physicians must . . .

9. BACKGROUND Subpart D of 45 CFR 46 governs pediatric research (1983)
Assent
“A child’s affirmative agreement to participate in research. Mere failure to object should not, absent affirmative agreement, be construed as assent”
IRBs
“shall determine that adequate provisions are made for soliciting the assent of the children, when in the judgment of the IRB the children are capable of providing assent”
Before Bullet #1 – Passage of federal regulations in 1983 that govern children’s research are specified in Title 45 Code of Federal Regulations Part
Federal regulations require that whenever possible, children provide their “affirmative agreement to participate in research,” or assent. Without getting too sidetracked, suffice it to say that this definition leaves something to be desired and like much of the controversy concerning assent (and trust me, there is one) is open to debate.
Before Bullet #3 - While the National Commission recommended investigators obtain the assent of all children, seven and older who are potential participants/subjects in research, federal regulations do not set a specific age limit, rather they leave the decision regarding determination of which children are capable of assent to local IRBs, stating . . .
After last bullet - Factors to be considered by IRBs in assessing capacity to assent include “ages, maturity, and psychological state of the children.”

10. PROBLEMS Vague and unclear Problems with CFR definition of assent
No specific age limit
Onus is on IRB
Flexible, yet fail to enumerate what is required with too little guidance as to what constitutes a meaningful concept of assent
Kimberely, et al. 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 2006;117:
Whittle, et al. Institutional Review Board Practices Regarding Assent in Pediatric Research. Pediatrics 2004;113:
Before bullet #1 - Rather than take a firm stand on assent, I believe that federal regulations are unrestrictive or vague. On one hand, they give IRBs free rein in their interpretation (as far as not establishing an age limit), yet they fail to enumerate what is exactly required for assent.
That said, such a policy is not entirely without merit. A degree of flexibility that accounts for an individual child’s abilities is necessary for establishing assent as a meaningful concept.
But, in adopting such a minimalist definition, current federal regulations offer far too little guidance as to a meaningful concept of assent. Evidence of this is seen in several recent studies where it was shown that IRBs differed substantially in how they operationally define assent and how they interpret the federal regulations as they relate to individual protocols.

11. MORE PROBLEMS Assent in 2009 No consensus Definition Age Participants
Government, Prof associations, Assent community
Definition
Age
Participants
Conflict resolution
Assent vs consent
Disclosure
Children’s desires
Assessment
Decision-making model
Because of time constraints I can’t go into too much detail, but I hope you can trust me when I say that assent is in the midst of an identity crisis of sorts. That said, progress has been made. A tremendous amount has been written about assent in the past 30 years, from a number of different of disciplines. The fields of medicine and nursing, philosophy and ethics, psychology, sociology, and anthropology all have made significant contributions to the discussion. However, this is part of the problem. Assent does not have a single home (and this may be a good thing).
There’s no consensus in guidelines disseminated by the government and professional associations, or even within the diverse “assent community.”
Controversial areas include the actual definition of assent.
How old kids should be in order to assent.
Who to include in the assent process.
What the relationship between assent and consent is.
The quantity and quality of information to disclose to kids and their parents.
The necessity and methods for assessing both children’s understanding of disclosed information and of the assent process itself, let alone an effective and practical decision-making model.
The analysis has become so fraught with complexity that some key contributors to the discussion suggest a transformation in the way assent is contemplated.

12. ASSENT  CONSENT
Children’s Views on Their Involvement in Clinical Research
Chappuy H, et al. Ped Blood & Cancer 2008;50:
“To examine the level of children’s understanding of informed consent in clinical trials & factors that may influence these processes”
“Determine children’s understanding of 9 items required in the informed consent document” *
An article published in a recent issue of Pediatric Blood and Cancer, illustrates some of the problems concerning assent. Twenty-nine children, 60% of whom had HIV, and 40% who had malignancies, from three French hospitals were the subjects of the study. The authors’ objective was to, “To examine the level of children’s understanding of informed consent in clinical trials & factors that may influence these processes.” The authors employed semi-directive interviews which were designed to “Determine children’s understanding of 9 items required in the informed consent document.”
The authors concluded that the children in their sample had limited understanding of the elements included in informed consent forms (this is not all that different from parents by the way). They also concluded that understanding was influenced by age, with children older than 14y having greater understanding. The authors then stated, “the challenge for the investigator is to determine the age or developmental level at which assent should be sought ”
This study is an important one. However, there are several significant problems with this study, that highlight some of the problems I’ve just mentioned. In their objective and again in describing their interview process, the authors clearly state that they sought to determine what children understood about informed consent. I would go so far as to say that the merits of this study aside, by focusing on kids’ understanding of informed consent, the authors are essentially shooting themselves in the foot [and simultaneously serving the interests of the assent critics]. While this may not have been their intent, what is clear is that like so many others before them, the authors have conflated consent and assent. Just like children aren’t “little adults,” assent is not consent. Assent must be viewed on its own, independently of consent. Equating assent and consent does a disservice to both principles and is bound to fail. Assent is not the ugly stepchild of consent.
Viewing assent as a corollary of consent overemphasizes the importance that children understand risks and benefits. Many IRBs and investigators are comfortable with this approach, and in doing so they essentially adhere to adult research regulations, using it as a default when examining assent. The problem with equating assent and consent is that it holds children to an unfair standard with the potential for limiting their ability to participate in research at all. [You don’t have to take my word alone for this, Skip Nelson, a pediatric anesthesiologist, who formerly served as the chairman of the FDA’s Pediatric Advisory Committee, and who is now the FDA’s chief ethicist at the Office of Pediatric Therapeutics shares this view as do other prominent pediatric bioethicists.]
The second problem with the study is the authors reliance on the informed consent form. Assent, and consent for that matter, is not about a form. It is well known that IRBs and individual investigators have a tendency for over-relying on assent and consent forms. While (assent/consent) forms have a place in the assent process, their use is associated with an over estimation of their utility. The mere signature of a child on the last page of what is often a long, complicated, and unwieldy document, incorporating language and terminology that is difficult to comprehend even by adult standards, fails to meet necessary standards for soliciting meaningful assent. Moreover, such a view of assent and consent fails to appreciate that both principles are processes, and are not simple transactions like buying a car, which is essentially a “sign-and-done deal,” never to be revisited.
The last problem with the study is the emphasis on the nine elements of informed consent. Compared with adults, a less exacting capacity for decision-making is necessary for a child to meaningfully assent. Children do not need to understand all elements of consent when they assent to research. In fact, they only need to meet three criteria, (1) their choice must be voluntary, (2) their choice must be both reasonable and rationale, and (3) the child must understand information relevant to their choice. The notion of consent for adults is based on the principle of autonomy, which in turn focuses on competence, a legal term. Assent on the other hand is better viewed as focusing on capacity, a developmental term. Such an approach is a more appropriate way to think about assent and is a better point on which to base assent.

13. ASSENT IN 2009
ASSENT IN 2007

14. Does anyone in the audience work for Pfizer
Does anyone in the audience work for Pfizer? I ask because this slide was originally used by Pfizer in their effort to market viagra to women. What the Pfizer executives were trying to show was that male erectile dysfunction was a simple physiologic problem, amenable to correction by flipping a single switch, while female sexual dysfunction was considerably more complex.
I don’t mean to oversimplify consent, but I like this slide because I think that one could easily replace “men” with consent, and “women” with assent in an effort to capture how difficult a concept assent really is.

15. BACKGROUND Components of valid assent
Determine children’s understanding
Preferences for involvement
Children & the therapeutic misconception
Like others who are concerned with and who care for sick children, I share the belief that children should be included and involved in decisions about their care to the extent that they are able to and want to, which brings me to the topic of my own research – pediatric assent.
I shared the leukemia schema with you for a reason, because I think it helps illustrate how daunting a task it is for anyone, adult or child, to truly understand much of the research that they are involved in.
I believe that there are two particular areas of assent that are overlooked and which deserve further exploration - children’s understanding and their preference for being included in decisions about their care. Without an appreciation for these two areas, assent will continue to remain as its critics claim, a meaningless concept.
Specifically, I’m interested in figuring out what children who are enrolled in pediatric oncology research protocols understand about research, their research-related treatment, and their preferences (if any) for being included in decisions about their care.
Bullet #3 – A few slides ago I mentioned how both adult research subjects and physicians often fail to appreciate that the overarching objective of research is not the same as that of clinical care, what is known as the therapeutic misconception. In children, there are relatively few studies that have taken a look at the extent of children’s understanding and their desire to be included in research-related decisions and most of these have studied healthy children using hypothetical cases and on the decision-making preferences of adolescents with cancer (i.e., not younger children). This is where my study comes in.

16. METHODS Sample Survey instrument (QuAs)
7-18 year olds with cancer who have assented to therapeutic clinical trials
Survey instrument (QuAs)
Closed-ended
Open-ended
The hospital where I conducted the study, CNMC, follows federal regulations that require the assent of all children ages 7-18 years old who are involved in human subjects research. To try and answer the two questions that I posed, that is, what children who are enrolled in pediatric oncology research protocols understand about the research they’re involved in and what are their preferences for being included in decisions about their care, I came up with a survey instrument, called the quality of assent survey (QuAs).
The instrument is modeled after Steve Joffe’s quality of consent tool with adults and consists of 69 questions, most of which are multiple choice with some short answer questions.
I developed the two-part instrument after a literature review examining usage of existing questionnaires regarding children’s, parents’, and providers’ concerns. In addition to adapting questions from these tools, I also developed novel questions. To assure content validity and clinical relevance, a preliminary version of the instrument was reviewed by pediatric hematology/oncology professionals familiar with research trial methodology and child development and the updated instrument was then evaluated by a social scientist with expertise both in bioethics and in survey development. To determine if children were easily able to understand the instrument and the intent of its questions, the instrument was pre-tested in a convenience sample of healthy children and children with cancer, and where necessary, I made changes to the instrument (e.g. simplified wording). I then completed nearly forty face-to-face interviews with children between the ages of 7-18 who were subjects of a range of therapeutic clinical research trials (pilot, phase I, II, and III studies).
[What I’ve found out has been pretty revealing.]

17. METHODS Eligibility criteria Sixty-two children Documented malignancy
Age 7-18 years
Assented to a COG / PBTC research protocol
Sixty-two children whose cancer was diagnosed between ages 7-18y and who had assented to a COG/PBTC research protocol between January 2005 – September 2007, as evidenced by their signature, were eligible.
I sent a cover letter explaining the study to each child's parent(s)/guardian(s) to obtain permission for their child's participation and a separate, age-appropriate cover letter for the child was included.

18. METHODS Study Procedure
Semi-structured, private, face-to-face, audio-recorded interviews
Respondents were given a questionnaire identical to the one used by the investigator
Questions were read aloud & children responded orally
Prompts were included to assure understanding
Interviews were transcribed verbatim & verified against the audiotape
I reviewed and explained the study purpose and procedures first with both child and parents present, and then again when the child was alone. Consent, and developmentally appropriate assent forms, were then signed after study purpose and procedures were re-explained and reviewed the second time. All but 5 interviews (which took place in children’s inpatient rooms because of medical circumstances) were conducted in a private lounge before or after a routine clinic visit or on a separate day altogether. This was done to avoid the effects of procedures, medications, stress, tension or pain, which could cloud a child’s judgment.
Each child was given a questionnaire identical to the one that I used and they followed along as I read each question aloud to them. Children then responded orally. I used this approach because combined oral and written presentation is an established effective method for improving understanding and comprehension. Based on their responses (i.e., initial understanding) prompts were included to assure that children comprehended each question’s intent. This allowed all children, regardless of their reading or writing ability, to participate effectively.
Interviews were transcribed verbatim and transcripts were verified against the audiotape.

19. CHILDREN’S UNDERSTANDING & PREFERENCES for RESEARCH INVOLVEMENT
Familiarity
Knowledge
Awareness
Understanding
Appreciation
Decision-making
Decisional priority
Types of decisions
Role in decision to enroll
Preferences / Perceptions
Suggestions
Two primary themes were identified as relevant to the aims of the study, (1) children’s understanding of research and (2) their preferences for decision-making. One of the main reasons so few studies exist examining children’s understanding relates to the inherent difficulty in assessing understanding, which is aggravated by the fact that there are really no good available tools available to do so. For this reason, and because understanding is multidimensional, I operationally defined comprehension or understanding of research according to five criteria: (1) familiarity; (2) knowledge; (3) awareness; (4) understanding; and (5) appreciation.
Composite scores were then computed and were examined for their relationship to age, gender, educational level, cancer type, trial phase and type, months since protocol enrollment, and ongoing versus completed treatment.
What I’d like to do next is to describe each of the five comprehension / understanding elements after which I’ll talk about the decision-making component of the study.

20. FAMILIARITY & KNOWLEDGE of RESEARCH
Research term
Study
Research
Protocol
Experimental
Trial
Enrollment
Randomization
Consent
Assent
Knowledge of research
Familiarity + being told about different ways to tx illness
To assess familiarity, children simply indicated whether they recalled having heard a given clinical research term from the options listed here (protocol, trial, study, experimental, etc).
Knowledge of research was measured by summing children’s responses to the nine “familiarity items” and recognition that trial participation was one way to treat their disease as reflected by their response to the question, “Before starting treatment, did your doctor meet with you to talk about the ways to treat your illness? This question reflected research knowledge in the sense that when their doctor discussed different ways to treat their illness, that is, standard of care on the one hand and a clinical research trial on the other, the assumption is that children could discriminate standard treatment from trial-related research treatment, and therefore they possessed some “knowledge” about research.

21. AWARENESS of RESEARCH Know tx is considered clinical research
Main reason for study participation is to improve care for future children with cancer
One reason for study participation is to determine effect(s) of tx(s)
Prior to starting tx, signed name to a form
Know that signing name means agreed to participate in a study
Read form
Child / Parent received copy of signed form
Awareness of research reflected children’s recognition both of the objectives of research, and of their own role in trial participation, based on their responses to 7 questions listed here – “know treatment is considered clinical research;” “main reason for study participation is to improve care for future children with cancer;” “one reason for study participation is to determine effect(s) of treatment(s),” etc.
As far as the last four questions, the very first sentence of assent and consent forms for research studies conducted at CNMC starts with the sentence, “We would like to invite you to be part of a research study at Children’s National Medical Center.” For this reason, and because the practice at CNMC is to provide each family with a copy of the form, I felt that these remaining four questions were an appropriate measure of research awareness.

22. UNDERSTANDING of RESEARCH
One reason my doctor is giving me the medicines (s)he is, is to compare (figure out) the effects (good & bad) of 2 or more different ways of treating other children who have the same type of illness as mine to see which is better
The treatment I get/got as part of the clinical research was chosen randomly (by chance, like flipping a coin) from 2 or more options
Compared to other treatment for my illness, my study does not have more risks or discomforts (bad things) associated with it
It is proven that the medicines I am getting are the best treatment for my type of illness
By being part of the study, I am helping my doctor learn about my illness & ways to help kids who will get sick like me in the future
I can withdraw (not be part of) from the study anytime my parents or I decide to withdraw
Children’s understanding of the nature of research was based on their responses to a series of questions relating to the components of research, such as: comparing known to unknown interventions, randomization, risk-benefit of research-related treatment compared to standard treatments, efficacy of treatment, generalizable knowledge, and voluntariness.
Children were then asked five additional questions relating to the purpose of research – do they know or are they aware of the purpose of their study; are they able to define the purpose; is their definition correct; do they know or are they aware of the goal of research; and is the goal they described correct. Responses were then coded as correct or incorrect as a reflection of understanding, where a correct response indicated understanding and a general understanding of research was operationally defined as the sum of correct responses to these eleven questions.

23. APPRECIATION of RESEARCH
Why did you decide to participate in a clinical research study?
My parents told me to
My doctor told me to
My parents & doctor told me to
To get better
To help other children
To help my doctor learn more about illness
Appreciation of research goals was determined by children’s reason(s) for participating in a research trial as reflected by their responses to the multiple choice question, “Why did you decide to participate in a clinical research study? “ Children were assigned a research appreciation score of 1-3, with 1 indicating less appreciation and 3 indicating greater appreciation, only if they selected from the last three options: “to get better,” “to help other children,” “to help my doctor to learn about my illness.”

24. DECISION-MAKING Decisional priority Types of decisions
Children’s overall involvement in decisions
Types of decisions
Major or minor
Role in decision to enroll
Very large, Large, Little, Very little, None
Preferences / Perceptions
Info, peer discussions, inclusion in decisions
Suggestions
For improving their role in decision-making
The second aim of the study was to determine children’s preferences for decision-making, here I assessed five separate elements based on children’s responses to five domains of research-related decision-making. Developmental scholars have established 14y as the age of abstract reasoning and the ability to comprehend a research agenda. Consistent with this practice, 14y was selected as the assessment point for the preference-related component of the instrument.
By decisional priority, my intent was determine the decision-making locus of control, that is, was it parents alone who were the primary decision-makers or were children included as well. If children were included, to know to what extent were they involved I asked children the following question, “Did anyone ever to talk to you about you getting to make decisions about your care? “
If children responded that they were involved in decisions, I asked them to give me an example of the kinds of decisions they made. I then classified the decisions as either “major” or “minor” based on a given decision’s potential impact on children’s disease. An example of a major decision was withholding medicines [vincristine because of neurotoxicity]; minor decisions were things like deciding to take pills versus tablets, how to have a procedure done, or who to tell they have cancer.
I determined children’s level of involvement in the actual decision to enroll in their trial based on their response to the question, “How much of a role did you have in the decision to be part of the clinical research?” Children selected from one of five options ranging from “very large” to “none.” Ten questions later in the survey, I asked them a related question, “Who made the decision about whether you were included in the clinical research study? “ The options here were,
My parents alone
My parents and my doctor
My parents and me
My parents, my doctor and me
Just me
My parents and other family members
My parents, other family members, and me.
Children then responded to a series of questions meant to gauge their preferences and perceptions for things like research-related information, peer discussions with other children enrolled in trials, and their desired level of inclusion in decision-making related to their care.
Finally, I concluded each interview by asking kids if they had any suggestions for how doctors could improve their role in decision-making.

25. Characteristic Number Percentage Gender Age (years) Males <14
Female 16 21 43 57
Age (years)
Males <14
Males >14
Females <14
Females >14 8 9 12 22 24 32
Cancer diagnosis
ALL
AML
CNS HD
NHL
GCT
Osteosarcoma
Ewing 11 3 6 2 1 30 5
Research protocol (phase)
Pilot
Phase I
Phase I/II
Phase II
Phase III
Biology 26 70
Months since protocol enrollment
< 4
4-12
12-24
>24 7 14 19 38 13
Treatment
Ongoing
Completed 23 62
As you can appreciate, the spectrum of cancer diagnoses of the 37 children who participated are representative of that seen in the general population. The respondents mean age was 13.6 years.

26. RESULTS Children Unaware their treatment is clinical research
Limited understanding of research *
Do not understand MD’s explanation *
Personal gain + Altruism *
Pressured to enroll *
Exclusion versus inclusion *
Reluctant to discuss decision-making *
Types of decisions – Minor
Want to make decisions
Desire parental + MD role *
Interested in research
The overwhelming majority of kids reported that when talking about their care, either their parents or doctor had used the words “research” (87%) or “study” (95%), yet over half (51%) did not know or did not recall being told that their treatment was considered clinical research.
On the whole, most children had a limited understanding of what research is despite doctors’ explanations. Children did understand some key features of research, for example, most children chose correctly that the goal of research is to help other children who will get cancer in the future, but most did not understand elements such as study-purpose, randomization, that their treatment might be more risky or less efficacious than standard treatments (73%), that the medicines they are getting have yet to be proven to be better than standard treatments (73%), or that they or their parents could withdraw from the trial at any time. Hyperlink
Less than a quarter of all kids said that the information about their trial was easy to understand at the time they had assented and those who did were almost exclusively older adolescents. Nearly all kids (86%) told me that they did not understand their doctor when (s)he spoke to them about their research study. Hyperlink
Kids' reasons for participating in research were not solely selfish; that is, asked to select their reasons for participating in clinical research, more kids said that they did so in order to help other kids who will get cancer in the future (73%) than to get better (60%), and nearly half (43%) said they participated in research to help their doctors to learn. Hyperlink
That said, most children enrolled in research protocols because their parents told them to, although older children were involved to some extent in the decision. In fact, half (49%) of the children said they had little to no role in the decision to enroll in the study and 38% of kids said they did not feel free to decline participating in research (dissent). The most common answer given for why they still went ahead with participating was because they felt pressured from doctors and parents. Hyperlink
Most children, 54% (n=20), responded that neither their parents nor doctor had talked to them about making decisions about their care and children who were spoken to were almost all older adolescents. Hyperlink
Also, the types of decisions most kids made were minor ones, which had little significance on their disease, examples include, how to take medicines (pill versus tablet), how to have procedures done, who to tell they’re sick. While 73% of children responded that they were involved in the decision to enroll in their clinical trial, nearly half (49%; n=18) of children reported they had “very little,” “little,” or “no role” in actually deciding to enroll in their study. The older the child, the more likely they were to be included in the enrollment decision, p=0.039.
Without exception, all the children in the study wanted to be involved to some extent in decisions about their care, but only 11% told their doctor, and only 19% told their parents, that they wanted to be more involved in decision-making. Hyperlink
At the same time, most children don’t want to be making decisions alone – 97% said they want their parents and 94% said they want their doctors to be involved too and they expect their doctors and parents to listen to them. Hyperlink
Not only do kids want information about the research they’re part of, they want to have a better understanding of what research is. 87% responded that they would find it helpful if someone would have explained to them why research is done, before they were asked to enroll, and more than half said they would have wanted the explanation even if it meant delaying the start of their treatment. Along this theme, 76% said they would have liked to speak to other kids with similar diagnoses, who are also enrolled in research protocols, to help them understand what being a research subject means.

27. Children’s Familiarity with Research Terminology, Research Knowledge, & Elements Comprising Awareness of Research Enrollment (n = 37)
FAMILIARITY (whether recall having heard items #1-9)
Research term
No.
% “Familiar”
Study 35 95
Research 32 87
Consent 25 68
Protocol 24 65
Experimental 21 57
Trial 15 41
Enrollment 13
Assent 12
Randomization 7 19
KNOWLEDGE (Sum of responses to 9 familiarity items + response to item #10)
Before starting treatment, did your doctor meet with you to talk about the ways to treat your illness? 26
% Answering “yes” 70
AWARENESS
% Answering “yes” or correct response†
Main reason for study participation is to improve care for future children with cancer 33
89†
One reason for study participation is to determine effect(s) of treatment(s)
Prior to starting treatment, signed name to a form
Child / Parent received copy of signed form
Read form 20 54
Know that signing name means agreed to participate in study 51
Know treatment is considered clinical research 18 49
Table 2 lists respondents’ familiarity with research terms and provides frequencies of children’s knowledge and awareness of research. Knowledge scores ranged from 1-10, mean=5.7 (95% CI: ). Awareness scores ranged from 2-7, mean=4.8 (95% CI: ).

28. RESULTS HD & GCT greater knowledge (mean=7.6) than “others” (mean=5.0)
HD, CNS, leukemia higher mean understanding (7.8, 7.5, 6.8) than “others” (mean 6.0)
Controlling for age, neither remained sig, p=0.38, p=0.22
Knowledge, awareness, understanding, & appreciation of research were not significantly associated with gender, protocol phase or type, months since diagnosis, or ongoing versus completed treatment
HD, GCT, leukemia significantly greater awareness (mean=5.5) & appreciation (mean=2.2) than “others” (mean 3.6 & 1.0)
Remained significant when controlling for age, p=0.019, p<0.001
Before Bullet #1 – For those of you who are craving some hard numbers, this slide is for you. Children with HD and GCT had greater knowledge (mean = 7.6) than children with other diagnoses (mean = 5.0) for a p value of 0.003, while children with HD, CNS tumors, and leukemia had higher mean understanding compared to children with other cancers (mean=7.8, 7.5, and 6.8 respectively), however, when controlling for age these were not significant, p = 0.38 and p=0.22 respectively.
Knowledge, awareness, understanding, & appreciation of research were not significantly associated with gender, protocol phase or type, months since diagnosis, or ongoing versus completed treatment.
One of the more revealing findings was that children with HD, GCT, leukemia had significantly greater awareness (mean=5.5) & appreciation (mean=2.2) than “others” (mean 3.6 & 1.0) and these remained significant when controlling for age, p=0.019, p<0.001.

29. CHILDREN’S SUGGESTIONS for IMPROVEMENT
“Talk to me (too)”
No “medicalese”
“Don’t assume”
Be honest / truthful
More choices / details
“Don’t focus on my age”
Offer advice
Finally, kids clearly had a preference for being involved in decisions about their care. Asked if they had suggestions for improving their role in decision-making, half of surveyed kids responded and most had several suggestions:
The most frequent suggestion was -
Children want doctors to talk directly to them and not only to talk to their parents.
Doctors need to do a better job making sure that what they say (to kids) is understandable.
Children want their doctors to ask them what their concerns are.
Kids expect their doctors to be truthful/honest about their diagnosis and prognosis.
When it comes time to decide on a treatment plan, kids want to be offered more choices.
Kids don't want to be treated like children merely based on their age.
And finally, kids want to be offered more details and for their doctors to give them advice on how to cope with their illness.

30. DISCUSSION
Irrespective of age, children with HD, GCT, & leukemia had sig greater awareness & appreciation of research (p=0.019, p<0.001)
?Outcome-related
?Altruism
Decisional priority + Pressure to enroll
The findings show that children’s understanding and knowledge of research, physicians’ willingness to broach decision-making, types of decisions children make, and children’s roles in the actual decision to enroll in research studies were all age-dependent.
None of the examined themes [Knowledge, awareness, understanding, and appreciation] were significantly associated with gender, protocol phase or type, months since diagnosis, or ongoing versus completed treatment. However, irrespective of age, children with HD, GCT, and leukemia had significantly greater awareness and appreciation than children with other cancers. Just to remind you, awareness reflected children’s recognition of research objectives and of their own role in trial participation - knowing that their treatment was considered research; that the main reason for their being enrolled in a study was to come up with improved treatments for future children with cancer or to determine the effects of a given treatment. Appreciation was based on children’s reasons for participating in research, where a higher score was given to children who said, “to get better,” “to help others,” and/or “to help my doctor to learn.” Both these relationships remained significant when controlling for age.
One possible explanation for this may be related to outcome. As a group, overall survival for children with HD, GCT, and leukemia is considerably better compared to children with other cancers. Parents and physicians may be more willing to talk to children who have a greater likelihood of survival than they are to children who do not. Parents and physicians may also tell these children different things about the studies they are part of which might explain their greater awareness and appreciation. These speculations require future examination.
More children reported enrolling in research studies to help future children with cancer than to get personally better and nearly half enrolled to help their doctor to learn. These findings indicate that altruistic motives may play a role in children’s reasons to enroll in oncology trials. Like the larger pediatric oncology population, most children in our study were in phase III trials, where the direct therapeutic benefit is expected to be at least as effective as standard interventions. When I first saw this finding, I thought that perhaps children (at least those in phase III trials) appreciated the intricacies of trial design to such an extent, that they knew that because they were assured of getting the current best treatment, they had “nothing to lose” by being altruistic. However, our findings showed no link between trial phase and children’s understanding, awareness or appreciation. In other words, the kids weren’t so savvy when it came to understanding this particular aspect of research. What then is the reason behind their possible altruism? Whatever their reason(s), our findings suggest that children already consider altruistic motivations and thus exploring these considerations with them may be appropriate.
Additionally, our data support previous findings that children often enroll/remain in studies because of parental/physician pressure. Many children stated that ultimate decisional priority resided with parents/doctors and that their own voices bear little influence on the important decision of whether to enroll in a clinical trial. This might explain why despite their desire to be included in decision-making, so few children actually spoke to parents/doctors about increasing their decision-making role. These findings suggest that parents/physicians could do more to involve children in decision-making to avoid forcing them to enroll in trials. The AAP recommends that children be included in decision-making. Since there appears to be morally relevant differences for children’s reasons to enroll in oncology trials - the desire to help future children with cancer and to assist physicians acquire knowledge; the fear of being treated differently by doctors by refusing trial participation; avoidance of physician and parental pressure to participate in trials; and the fear of disappointing parents by not participating - a greater focus on children who enroll in research because their parents/doctor tell them to is needed. Perhaps these children have a better appreciation of research based on their perception of decision-making control and the limited role they have in it.

31. LIMITATIONS Single investigator-single institution, pilot study
Responses may not reflect actual beliefs, but what children think investigators want them to say
Interviews occurred after children had assented to research enrollment
Findings reflect reports of children only
There are several limitations to this study. First, while the sample was representative of the larger population of children with cancer it was conducted by a single investigator at a single institution. Moreover, the sample size was small, although adequate for a pilot study. Additional investigation is required to determine if the results are generalizable to other populations.
Second, children’s responses may not reflect their actual beliefs, but what they think investigators want them to say.
Third, because interviews occurred after children had assented to research enrollment they had to recall past events and their preferences may have changed over time, which may have affected the accuracy of responses. Ideally, interviews should be done in “real time.”
The second and third limitations are shared by many questionnaire-studies. The semi-structured nature of the study, incorporating open-ended questions, allowed for a richer determination of children’s views and minimized these negative potentialities.
Finally, findings reflect reports of children only. Parents and physicians weren’t surveyed; therefore, the results are not completely comprehensive.

32. IMPLICATIONS Clinical trials Improve understanding
Gold standard in pediatric heme/onc
Improve understanding
Greater decision-making role
When appropriate
As I see it, there are several potential implications of my study. First, it’s clear that children want to be involved in decisions about their care, yet many parents and physicians fall short in including children in decisions about their care. Second, for the most part, children do not understand much of the research they are part of, and despite the Belmont Report and the AAP’s recommendations that investigators verify that research subjects understand research-related information, many physicians do not determine if children understand what it is they are assenting (agreeing) to being part of.
Given that the pediatric oncology community considers clinical trials the gold standard, pediatric oncologists will continue to enroll as many children as possible in research protocols. Therefore, it is imperative that individual pediatric oncologists and the profession as a whole pay attention to the writing on the wall.
There are two immediate problems which need to be overcome, the first is limited time, the second is that pediatric oncology professionals may lack the necessary skills to assess every child’s particular level of understanding. What I envision is that upon completion of the assent / consent conference and prior to soliciting a child’s assent, either doctors or research-nurses can use an instrument similar to one I have come up with as a generalizable tool to clarify topics that children themselves describe as poorly understood. As a consequence, physician-investigators will be better equipped to include children as active participants in research, rather than as mere subjects. Using such a tool should help physician-investigators to meet both the Belmont Report and the AAP’s requirement that investigators ascertain comprehension, as well as help equip children with the tools needed to give a more valid assent and otherwise participate more meaningfully in research.
My next area of investigation involves validating a modified version of the QuAs instrument; it is easy to administer (30 questions and <15 minutes), applicable to a range of clinical trials, and suited to alleviate some of the obstacles I’ve just described and to assist professionals in assessing systematically children’s understanding.
With regard to children’s involvement in decisions related to their care, here too the onus is on us (physicians). We (Physicians) must educate families about a child’s condition and options and establish that both parents and children understand theirs, as well as each other’s role and responsibilities. We (Physicians) need to emphasize that effective communication is a pre-requisite for shared decision-making, which in turn provides a strong foundation on which to base assent.

33. beginning. [Things like] Facts & previous outcomes from
Present me with more choices for treatment in the
beginning. [Things like] Facts & previous outcomes from
treatments they've given. I know decisions sometimes are
needed in a short amount of time, but sometimes you need a
little time to think about what's going to happen - at least
just ask. Just because I am deemed a child because I'm less
than 18, I don't think I should be treated like a full child
when it comes to my health I need doctors' advice, but
sometimes I want to decide & not be written off & treated
like a child because I'm under 18
17 year-old
The following statement by a 17-year-old is especially perceptive. It highlights many of the suggestions children had regarding their role in therapeutic trials.

34. LET ASSENT OUT ITS CAGE