Abstract
Objectives:
To assess the US public’s views on whether the potential medical benefits of phase 1 pediatric oncology trials justify the risks.
Study design:
Online survey of a nationally representative sample of US adults. Participants were presented with a hypothetical scenario in which they have a 10-year-old child with advanced cancer. They were then offered the option of giving their child supportive care or trying one more potential treatment, in the research or clinical care setting, which has the same risks and potential medical benefits as the average phase 1 pediatric oncology trial. We assessed what percentage of respondents thought the potential medical benefits justify the risks.
Results:
1658 of the 2508 individuals who were sent the survey participated (RR= 66.1%). Of those who passed all three test questions indicating understanding, 67.1% in the research scenario and 58.5% in the clinical care scenario regarded the potential medical benefits of an average phase 1 pediatric oncology trial as equal to or greater than the risks. In addition, 53.4% of respondents in the research scenario thought it was appropriate for researchers to conduct a study in children with these risks and potential medical benefits, and 46.9% stated they would enroll their own child in such a trial.
Conclusions:
A majority of the US public regards the potential medical benefits of average phase 1 pediatric oncology trials as justifying the risks. This finding suggests that these trials are ethically appropriate and approvable in patients who have no more effective treatment options. At the same time, a significant minority thought the potential medical benefits do not justify the risks, suggesting these trials should be approved only when they have significant social value. Moreover, approximately half of respondents regarded the trials as inappropriate and would not enroll their own child, underscoring the need for a rigorous informed consent process which accurately educates parents regarding the risks, potential medical benefits and alternatives, so they can decide whether to enroll their child based on their own preferences and goals.
Phase 1 pediatric oncology trials, which test the safety and tolerability of experimental cancer drugs and interventions, are vital to improving treatments for children with cancer. Yet, these trials pose significant risks and offer a very low chance of medical benefit to minors with advanced cancer. As a result, there remains significant debate over whether these trials are ethical and approvable.[1–3]
Some commentators attempt to resolve this debate by appeal to theoretical considerations. They consider whether investigators intend to benefit participants,[3–5] or whether the purpose or goal is to benefit participants.[6,7] Still others consider whether enrollment offers any chance for medical benefit.[8] These factors, although important, do not determine whether pediatric trials that pose significant risks are ethical and approvable. That depends, in the words of the US regulations, on whether the risks are “justified” by the potential medical benefits and whether the study’s risk-benefit profile is “at least as favorable” as any available alternatives.[9]
A few commentators have previously tried to assess the first condition, whether the potential medical benefits of phase 1 oncology trials justify the risks, using empirical data.[6,10,11] Kimmelman argues: “The assertion that phase I trials offer a vehicle for pursuing cancer treatment (the ‘therapeutic position’) rests on weak evidence.”[12] These critics worry that phase 1 pediatric oncology trials might take advantage of parents who underestimate the risks and overestimate the potential medical benefits out of desperation. Others argue that phase 1 oncology trials offer a reasonable treatment option for many patients.[4,13] For example, a working group convened by the American Society of Clinical Oncology argues for the “critical importance of phase 1 trials” in the treatment of cancer.[14]
These previous assessments have relied largely on data from adult trials. More recently, systematic data on phase 1 pediatric oncology trials have become available.[15] These data offer the opportunity to assess whether the potential medical benefits of phase 1 pediatric oncology trials justify the risks. Unfortunately, there is no algorithm which can be used to compare potential medical benefits and risks to determine definitively which are greater. A standard alternative is to assess whether informed and reasonable individuals regard the potential medical benefits as justifying the risks. We thus conducted a survey of a nationally representative sample of the US public to answer the following question: Do respondents think the potential medical benefits of average phase 1 pediatric oncology trials justify the risks? The findings offer important data for assessing the ethics and approvability of phase 1 pediatric oncology trials, as well as early phase trials in pediatric patients more generally.
Methods
Participants were drawn from Ipsos KnowledgePanel, the largest online research panel representative of the US population. KnowledgePanel is widely used by academic, government, and commercial researchers and consists of 55,000 members. Ipsos randomly recruits panel members through address-based sampling methods. Members are provided with internet and hardware if needed, which allows for recruiting harder-to-reach individuals. Study samples are constructed to be representative by weighting responses to the geodemographic benchmarks from the most recent US Census Bureau’s Current Population Survey. After data are collected, any differential nonresponses are addressed by adjusting the weights so that the final, weighted sample is representative of the US population (Table 6 [available at www.jpeds.com] shows data on sample representativeness).
Table 6.
Sample Representativeness
| 18+ US Population Benchmarks Source: March 2019 CPS Supplement Data | Unweighted Sample | Weighted Sample | ||||
|---|---|---|---|---|---|---|
| Age/Gender | Frequency | Percent | Frequency | Percent | Frequency | Percent |
| Age 18–29 Male | 26396317 | 10.54 | 118 | 7.12 | 174.7539 | 10.54 |
| Age 18–29 Female | 25955786 | 10.36 | 103 | 6.21 | 171.8374 | 10.36 |
| Age 30–44 Male | 31177102 | 12.45 | 185 | 11.16 | 206.4046 | 12.45 |
| Age 30–44 Female | 31748359 | 12.68 | 200 | 12.06 | 210.1865 | 12.68 |
| Age 45–59 Male | 29954109 | 11.96 | 225 | 13.57 | 198.3079 | 11.96 |
| Age 45–59 Female | 31887366 | 12.73 | 221 | 13.33 | 211.1068 | 12.73 |
| Age 60+ Male | 33719599 | 13.46 | 286 | 17.25 | 223.2369 | 13.46 |
| Age 60+ Female | 39599755 | 15.81 | 320 | 19.3 | 262.1658 | 15.81 |
| Ethnicity | ||||||
| White, Non-Hispanic | 1.58*108 | 63.14 | 1145 | 69.06 | 1046.941 | 63.14 |
| Black, Non-Hispanic | 29591920 | 11.82 | 157 | 9.47 | 195.9101 | 11.82 |
| Other, Non-Hispanic | 18016857 | 7.19 | 85 | 5.13 | 119.2786 | 7.19 |
| Hispanic | 41183699 | 16.44 | 220 | 13.27 | 272.6522 | 16.44 |
| 2+ Race, Non-Hispanic | 3507129 | 1.4 | 51 | 3.08 | 23.21857 | 1.4 |
| Region | ||||||
| Northeast Metro | 40562599 | 16.2 | 279 | 16.83 | 268.5403 | 16.2 |
| Northeast Non-metro | 3166738 | 1.26 | 26 | 1.57 | 20.96504 | 1.26 |
| Midwest Metro | 41266805 | 16.48 | 267 | 16.1 | 273.2024 | 16.48 |
| Midwest Non-metro | 10775725 | 4.3 | 73 | 4.4 | 71.33951 | 4.3 |
| South Metro | 81209271 | 32.43 | 518 | 31.24 | 537.6371 | 32.43 |
| South Non-metro | 13796808 | 5.51 | 98 | 5.91 | 91.34026 | 5.51 |
| West Metro | 53986640 | 21.56 | 362 | 21.83 | 357.4126 | 21.56 |
| West Non-metro | 5673809 | 2.27 | 35 | 2.11 | 37.56283 | 2.27 |
| Education | ||||||
| Less than HS | 26545840 | 10.6 | 148 | 8.93 | 175.7438 | 10.6 |
| High school | 70902256 | 28.31 | 464 | 27.99 | 469.4006 | 28.31 |
| Some college | 69536578 | 27.77 | 445 | 26.84 | 460.3593 | 27.77 |
| Bachelor’s or higher | 83453720 | 33.32 | 601 | 36.25 | 552.4962 | 33.32 |
| Income | ||||||
| Under $25,000 | 33939640 | 13.55 | 173 | 10.43 | 224.6937 | 13.55 |
| $25,000–$49,999 | 45566237 | 18.19 | 305 | 18.4 | 301.6663 | 18.19 |
| $50,000–$74,999 | 43107614 | 17.21 | 265 | 15.98 | 285.3892 | 17.21 |
| $75,000–$99,999 | 34393082 | 13.73 | 272 | 16.41 | 227.6956 | 13.73 |
| $100,000–$149,999 | 44338601 | 17.7 | 302 | 18.21 | 293.5389 | 17.7 |
| $150,000 and over | 49093220 | 19.6 | 341 | 20.57 | 325.0163 | 19.6 |
Selected members were notified by email that the survey was available. Three reminders were sent over an 18-day period. To be eligible, participants had to be 18 years or older and have English language proficiency.
Participant Protection
The study was deemed exempt from US regulations by the NIH intramural IRB. No personally identifiable information was collected. Potential participants were informed that participation was voluntary, they could skip any questions they did not want to answer and they could stop the survey at any time. Each MTurk participant in our piloting testing was compensated $2. KnowledgePanel participants in the main phase were compensated per their membership agreement.
Survey Design and Development
The survey was drafted based on a comprehensive review of the literature on pediatric research and phase 1 trials. We then solicited input from experts in these fields and revised the instrument accordingly. The draft survey underwent two rounds of review and revision based on input from members of the NIH Department of Bioethics Empirical Research Laboratory. The revised survey was piloted in four rounds of testing using Amazon Mechanical Turk (MTurk), a crowdsourcing marketplace where anonymous individuals complete online tasks (such as surveys), with 555 respondents. Revisions were made after each round.
The final survey addressed four domains: 1) respondent characteristics; 2) risks and medical benefits of phase 1 pediatric oncology research; 3) risks and societal benefits of non-beneficial pediatric research (data reported elsewhere, under review); and 4) attitudes toward research (adapted from Rubright et al40). This article reports on the results from the first, second, and fourth domains.
We hypothesized that respondents might regard the potential medical benefits of average phase 1 pediatric oncology trials as not justifying the risks simply because the treatments are offered in the research rather than the clinical setting. To assess this possibility, we randomized respondents to a research or a clinical care scenario in domain 2 of the survey.
To approximate the circumstances of children who are eligible for phase 1 oncology trials, the research and clinical care scenarios asked respondents to imagine they have a 10-year-old with advanced cancer who has two remaining options. The two options were described, in the research scenario, as enrolling their child in a “research study testing an experimental cancer treatment” or providing their child with “pain medicine to keep your child as comfortable as possible until she dies, which will probably happen in a few months” (see supplemental information for the complete wording). The two options in the clinical care scenario were described in the same way, except that the treatment was described as “one more possible treatment” that could be provided by the child’s doctor.
Estimating the Risks and Potential medical benefits
To estimate the potential medical benefits and risks of average pediatric phase 1 oncology trials, we used a meta-analysis by Waligora et al, supplemented with previous meta-analyses of phase 1 oncology studies in children and adults.[15–25] With respect to potential medical benefits, Waligora et al found a partial or complete response rate of 10.3%. This is similar to the 9.6% response rate found by Lee et al, which analyzed pediatric phase 1 studies, and the 10.6% response rate found by Horstmann et al, which analyzed adult phase 1 oncology studies.16,26 In contrast, Wong et al found a 2.95% response rate in adults.19 The response rates in these studies were based on solid tumor and hematological malignancies combined. Other reviews found a response rate in solid tumors of 7.2%,[17] 4%,[25] and 3.8%,[18] which is consistent with the 3.2% solid tumor response rate found by Waligora et al. Based on these findings, we described the chance for medical benefit in both scenarios as follows:
“There is a 1 in 10 chance that taking the experimental (possible) treatment will cause your child’s cancer to shrink. There is a small chance that your child will feel better as a result. It is possible, but very unlikely, that your child will live longer as a result of taking the experimental (possible) treatment.”
With respect to risks, Waligora et al found an overall death rate of 2.09% and an average grade 3 or 4 adverse event rate of 1.32 per person.[15] This death rate is higher than what previous reviews of pediatric studies have found, which include 0.4%[25] and 0.5%,[26] but consistent with the 1.9 – 2.3% (adult) death rate found by Schwaederle et al.[22] Waligora et al also found a higher adverse event rate than what previous reviews of pediatric and adult studies have found.[15] Lee et al found the likelihood of experiencing a dose-limiting toxicity (DLT) to be 24% among pediatric patients, and Kim et al found a pediatric DLT rate of 17%.[25,26] Fukuda et al found a grade 4 toxic event rate (in adult phase 1 oncology studies) of 19.9% and Roberts et al found a grade 3 and 4 toxic event rate (in adult solid tumors) of 10.3%.[18,24] Given that other meta-analyses of pediatric (and adult) studies found lower death rates and adverse event rates, we described the risks in both scenarios as follows:
“There is a high chance your child will experience a serious side effect from taking the experimental (possible) treatment, such as significant nausea, pain, or hospitalization. Also, there is a 1 in 100 chance your child will die as a result of taking the experimental (possible) treatment.”
Survey Questions
Following description of the research and clinical care scenarios, participants were asked three “test” questions (see supplemental information) to ensure they accurately understood the experimental (or possible) treatment’s risks and potential medical benefits. Following the test questions, participants were asked how they thought the risks and potential medical benefits compare.
Pediatric research raises ethical concern when it exposes participants to ‘net’ risks in order to collect data that might benefit future patients. This occurs when the risks of the research outweigh the potential medical benefits and also when the risk-benefit ratio is less favorable than the risk-benefit ratio of one or more available alternatives. In contrast, pediatric research that has important social value and does not expose participants to net risks is ethically acceptable with respect to risks and benefits. This occurs when the potential medical benefits are equal to or greater than the risks, and there is no alternative that offers participants a more favorable risk-benefit ratio.
US federal regulations describe the requirement that the potential medical benefits are equal to or greater than the risks in terms of the risks being “justified” by the potential medical benefits. We were concerned that some respondents might find this wording confusing. As a result, the survey offered respondents the following five answer options: “The potential medical benefits definitely outweigh the risks”; “The potential medical benefits probably outweigh the risks”; “The potential medical benefits and risks are about equal”; “The risks probably outweigh the potential medical benefits”; and “The risks definitely outweigh the potential medical benefits.”
Combining the first three answer options provides an estimate of how many respondents regard the average phase 1 pediatric oncology trial as posing no net risks to participants.[27] We regard this group as believing that the potential medical benefits justify the risks; hence, in the absence of any better alternatives, the trial is ethical with respect to risks and potential medical benefits. Combining the last two answers provides an estimate of how many respondents regard participation as posing net risks. We regard this group as believing that the potential medical benefits do not justify the risks; hence, the trial raises ethical concern with respect to risks and potential medical benefits.
Participants were also asked whether they thought, given the risks and potential medical benefits, and absence of any treatment alternatives, it was appropriate to offer children the experimental (or possible) treatment and how likely they would be to enroll (or give the possible treatment to) their child. Finally, we asked participants whether it can be appropriate to enroll children for non-medical reasons in trials whose risks definitely outweigh the potential medical benefits. Respondents who indicated that this can be appropriate were asked specifically about the appropriateness of the following reasons: “participation offers a way for the parents and the child to help other children with cancer”; “participation offers a way for the parents and the child to continue to fight the disease and maintain hope that the child might get better”; “participation provides a way to bring some meaning to a bad situation”; “participation provides a way for parents to make some money”; and “participation is the only option for treating the child’s disease.” It is widely agreed that it is not appropriate for parents to enroll their children in research to make money. We thus included this question as a control to assess whether participants were simply indicating that the offered reasons were appropriate without considering them carefully.
Statistical Analyses
We based our sample size calculation on the primary outcome question of whether the potential medical benefits of the possible treatment outweigh the risks. To achieve a two-sided 95% confidence interval with a width of 5%−8% and a sample proportion in the range of 30% to 80% required 800 respondents in each of the two scenarios. We analyzed the subset of respondents in each scenario (about 500 respondents each) who answered all three test questions correctly. With about 500 respondents, the confidence interval width remains about 8%. The study was administered using the survey platform Qualtrics and data were analyzed using SAS (Version 9.4).
Descriptive statistics were generated for the sample’s sociodemographic characteristics. Weighted summary statistics such as proportions were calculated using SAS procedure SURVEYFREQ for respondents’ answers to the outcome questions, including those assessing the hypothetical study’s risk/benefit profile, the appropriateness of the study, whether respondents would enroll in it, and whether non-medical reasons for participating are acceptable. Chi-squared tests were used to explore any differences in how the outcome questions were answered depending on participants’ responses to our test questions.
Associations between sociodemographic variables, including gender identity, age, race, ethnicity, income, education, geography, having children, prior research participation, and general attitudes toward research, and the primary outcome questions were also tested using chi-squared tests. A p-value of less than 0.05 was used to indicate statistical significance.
Results
Of 2508 individuals who were sent the link, 1658 participated (RR= 66.1%). Overall, 844 (50.9%) participants identified as female and 814 (49.1%) as male; 1334 (80.5%) identified as White, 165 (10%) as Black, 74 (4.5%) as Asian and 85 (5.1%) as other; 220 (13.3%) identified as Hispanic (Table I).
Table 1:
Demographics of Survey Participants1
| Characteristic [N (%)] | All (N = 1658) | Clinical Cohort (N = 775) | Research Cohort (N = 794) | Missing2 (N = 89) |
|---|---|---|---|---|
| Gender Identity | ||||
| Male | 814 (49.1) | 393 (50.71) | 394 (49.62) | 27 (30.34) |
| Female | 844 (50.9) | 382 (49.29) | 400 (50.38) | 62 (69.66) |
| Age | ||||
| 18–29 | 221 (13.3) | 97 (12.52) | 116 (14.61) | 8 (8.99) |
| 30–44 | 385 (23.2) | 173 (22.32) | 191 (24.06) | 21 (23.6) |
| 45–59 | 446 (26.9) | 219 (28.26) | 202 (25.44) | 25 (28.09) |
| 60+ | 606 (36.6) | 286 (36.9) | 285 (35.89) | 35 (39.33) |
| Race | ||||
| White | 1334 (80.5) | 625 (80.65) | 641 (80.73) | 68 (76.4) |
| Black or African American | 165 (10) | 79 (10.19) | 73 (9.19) | 13 (14.61) |
| Asian | 74 (4.5) | 34 (4.39) | 35 (4.41) | 5 (5.62) |
| Other | 85 (5.1) | 37 (4.77) | 45 (5.67) | 3 (3.37) |
| Ethnicity | ||||
| Hispanic | 220 (13.3) | 101 (13.03) | 105 (13.22) | 14 (15.73) |
| Non-Hispanic | 1438 (86.7) | 674 (86.97) | 689 (86.78) | 75 (84.27) |
| Income | ||||
| Less than $25,000 | 173 (10.4) | 86 (11.1) | 76 (9.57) | 11 (12.36) |
| $25,000 – $49,999 | 305 (18.4) | 139 (17.94) | 147 (18.51) | 19 (21.35) |
| $50,000 – $74,999 | 265 (16) | 132 (17.03) | 121 (15.24) | 12 (13.48) |
| $75,000 – $99,999 | 272 (16.4) | 117 (15.1) | 142 (17.88) | 13 (14.61) |
| $100,000 – $149,999 | 302 (18.2) | 133 (17.16) | 151 (19.02) | 18 (20.22) |
| $150,000 or greater | 341 (20.6) | 168 (21.68) | 157 (19.77) | 16 (17.98) |
| Education | ||||
| Less than high school | 148 (8.9) | 66 (8.52) | 73 (9.19) | 9 (10.11) |
| High school | 464 (28) | 223 (28.77) | 220 (27.71) | 21 (23.6) |
| Some college | 445 (26.8) | 190 (24.52) | 225 (28.34) | 30 (33.71) |
| Bachelor’s degree or higher | 601 (36.2) | 296 (38.19) | 276 (34.76) | 29 (32.58) |
| Region | ||||
| Northeast | 305 (18.4) | 144 (18.58) | 151 (19.02) | 10 (11.24) |
| Midwest | 340 (20.5) | 170 (21.94) | 155 (19.52) | 15 (16.85) |
| South | 616 (37.2) | 287 (37.03) | 292 (36.78) | 37 (41.57) |
| West | 397 (23.9) | 174 (22.45) | 196 (24.69) | 27 (30.34) |
| Do you have any children? | ||||
| No | 546 (32.9) | 260 (33.55) | 264 (33.25) | 22 (24.72) |
| Yes | 1107 (66.8) | 514 (66.32) | 527 (66.37) | 66 (74.16) |
| Missing | 5 (0.3) | 1 (0.13) | 3 (0.38) | 1 (1.12) |
| Have any of your children ever had a serious illness? | ||||
| No | 886 (80) | 411 (79.96) | 425 (80.65) | 50 (75.76) |
| Yes | 218 (19.7) | 103 (20.04) | 101 (19.17) | 15 (21.21) |
| Missing | 3 (0.3) | 0 (0) | 1 (0.19) | 2 (3.03) |
| Have you ever enrolled in medical research yourself? | ||||
| No | 1490 (89.9) | 687 (88.65) | 727 (91.56) | 76 (85.39) |
| Yes | 159 (9.6) | 86 (11.1) | 64 (8.06) | 9 (10.11) |
| Missing | 9 (0.5) | 2 (0.26) | 3 (0.38) | 4 (4.49) |
| Have you ever enrolled any of your children in medical research? | ||||
| No | 1061 (95.8) | 495 (96.3) | 505 (95.83) | 61 (92.42) |
| Yes | 41 (3.7) | 18 (3.5) | 20 (3.8) | 3 (4.55) |
| Missing | 5 (0.5) | 1 (0.19) | 2 (0.38) | 2 (3.03) |
| Attitudes Toward Research | ||||
| Medical researchers can be trusted to protect the people who take part in their studies. | ||||
| Strongly disagree | 71 (4.3) | 29 (3.7) | 42 (5.3) | 0 (0) |
| Disagree | 189 (11.4) | 98 (12.6) | 91 (11.5) | 0 (0) |
| Neutral | 699 (42.2) | 349 (45) | 350 (44.1) | 0 (0) |
| Agree | 464 (28) | 227 (29.3) | 237 (29.8) | 0 (0) |
| Strongly agree | 75 (4.5) | 36 (4.6) | 39 (4.9) | 0 (0) |
| Missing | 160 (9.7) | 36 (4.6) | 35 (4.4) | 89 (100) |
| People have some responsibility to help others by participating in medical research. | ||||
| Strongly disagree | 88 (5.3) | 37 (4.8) | 51 (6.4) | 0 (0) |
| Disagree | 222 (13.4) | 98 (12.6) | 124 (15.6) | 0 (0) |
| Neutral | 568 (34.3) | 281 (36.3) | 287 (36.1) | 0 (0) |
| Agree | 531 (32) | 268 (34.6) | 263 (33.1) | 0 (0) |
| Strongly agree | 87 (5.2) | 55 (7.1) | 32 (4) | 0 (0) |
| Missing | 162 (9.8) | 36 (4.6) | 37 (4.7) | 89 (100) |
| Medical research is important for helping to improve health and combating disease. | ||||
| Strongly disagree | 30 (1.8) | 17 (2.2) | 13 (1.6) | 0 (0) |
| Disagree | 17 (1) | 10 (1.3) | 7 (0.9) | 0 (0) |
| Neutral | 162 (9.8) | 82 (10.6) | 80 (10.1) | 0 (0) |
| Agree | 767 (46.3) | 363 (46.8) | 404 (50.9) | 0 (0) |
| Strongly agree | 519 (31.3) | 266 (34.3) | 253 (31.9) | 0 (0) |
| Missing | 163 (9.8) | 37 (4.8) | 37 (4.7) | 89 (100) |
All data unweighted
“Missing” refers to the number of participants who exited the survey prior to being randomized to either the clinical or research scenarios, as well as prior to the “attitudes toward research” questions.
To assess whether respondents might regard the potential medical benefits as not justifying the risks simply because the treatment was offered in research, we randomized respondents to a research or a clinical care scenario. Overall, 794 were randomized to the research scenario and 775 to the clinical care scenario; 89 respondents answered the initial demographic questions and then stopped the survey.
Respondents’ Views
Overall, 63.0% (500/794) of the respondents who were randomized to the research scenario and 61.2% (474/775) who were randomized to the clinical care scenario answered all three test questions correctly. Of these “informed” respondents, 31.7% in the research scenario regarded the potential medical benefits of the experimental treatment as outweighing the risks, and 32.9% considered the risks to outweigh the potential medical benefits. In comparison, 32.1% in the clinical care scenario regarded the potential medical benefits of the possible treatment as outweighing the risks, and 41.6% considered the risks to outweigh the potential medical benefits (p = 0.008) (Table 5 [available at www.jpeds.com] provides a comparison of clinical care scenario responses between those who passed all three test questions and those who did not).
Table 5:
Primary Outcome Questions – Clinical Scenario1
| Question2 | All (N = 775) | Percent3 | Passed test questions (N = 474) | Percent3 |
|---|---|---|---|---|
| How do the potential medical benefits and risks compare? | ||||
| Potential medical benefits definitely outweigh risks | 109 | 16.2% | 42 | 9.5% |
| Potential medical benefits probably outweigh risks | 184 | 25.0% | 103 | 22.6% |
| Benefits and risks about equal | 205 | 27.2% | 126 | 26.4% |
| Risks probably outweigh potential medical benefits | 151 | 19.3% | 118 | 24.9% |
| Risks definitely outweigh potential medical benefits | 94 | 12.3% | 78 | 16.7% |
| Missing | 32 | 7 | ||
| Do you think it is appropriate to offer this possible treatment to children? | ||||
| Definitely not appropriate | 74 | 9.6% | 53 | 11.3% |
| Probably not appropriate | 233 | 31.3% | 165 | 35.7% |
| Probably appropriate | 336 | 43.8% | 201 | 41.9% |
| Definitely appropriate | 110 | 15.3% | 52 | 11.0% |
| Missing | 22 | 3 | ||
| How likely would you be to ask your doctor to give your child this possible treatment? | ||||
| Very likely | 122 | 17.4% | 51 | 11.3% |
| Likely | 291 | 38.6% | 164 | 34.6% |
| Unlikely | 208 | 27.0% | 143 | 30.7% |
| Very unlikely | 133 | 17.0% | 111 | 23.3% |
| Missing | 21 | 5 |
Counts unweighted, proportions weighted
For verbatim wording of the questions, see supplemental information
Respondents who did not answer the question (“Missing”) are not included in the percent calculation
Combining the respondents who regarded the potential medical benefits as outweighing the risks with those who considered the potential medical benefits and risks to be “about equal,” 67.1% of informed respondents in the research scenario versus 58.5% in the clinical care scenario thought the potential medical benefits justify the risks in the sense that the research does not pose net risks to participants (p = 0.009). These findings suggest that the setting of research itself did not result in respondents assuming that the potential medical benefits of experimental treatments fail to justify the risks. As a result, the remainder of the analyses focus on the results from respondents who were randomized to the research scenario.
Of the respondents in the research scenario who passed all three test questions, 53.4% thought it was probably or definitely appropriate for researchers to conduct a study in children with the risks and potential medical benefits of average phase 1 pediatric oncology trials, and 46.9% stated they would likely or very likely enroll their children in such a study (Table 2).
Table 2:
Primary Outcome Questions – Research Scenario1
| Question2 | All (N = 794) | Percent3 | Passed test questions (N = 500) | Percent3 |
|---|---|---|---|---|
| How do the potential medical benefits and risks compare? | ||||
| Potential medical benefits definitely outweigh risks | 72 | 9.4% | 27 | 5.3% |
| Potential medical benefits probably outweigh risks | 202 | 25.9% | 132 | 26.4% |
| Potential medical benefits and risks about equal | 250 | 33.7% | 172 | 35.4% |
| Risks probably outweigh potential medical benefits | 155 | 19.6% | 111 | 21.8% |
| Risks definitely outweigh potential medical benefits | 84 | 11.3% | 54 | 11.1% |
| Missing | 31 | 4 | ||
| Do you think it is appropriate for researchers to conduct this study in children? | ||||
| Definitely not appropriate | 86 | 11.5% | 55 | 11.1% |
| Probably not appropriate | 255 | 34.1% | 170 | 35.5% |
| Probably appropriate | 363 | 46.0% | 233 | 46.4% |
| Definitely appropriate | 68 | 8.4% | 37 | 7.0% |
| Missing | 22 | 5 | ||
| How likely would you be to enroll your child in this study? | ||||
| Very likely | 79 | 9.4% | 45 | 8.4% |
| Likely | 301 | 39.0% | 192 | 38.5% |
| Unlikely | 221 | 29.4% | 143 | 29.6% |
| Very unlikely | 174 | 22.1% | 118 | 23.5% |
| Missing | 19 | 2 |
Counts unweighted, proportions weighted
For verbatim wording of the questions, see supplemental information
Respondents who did not answer the question (“Missing”) are not included in the percent calculation
Sociodemographic Characteristics and Risk/Benefit Assessment
Bivariate analyses were conducted to assess for any associations between respondents’ sociodemographic characteristics and their evaluation of whether the potential medical benefits outweigh the risks (Table 3). Only research scenario respondents who passed all three test questions (N = 500) were analyzed, and weighted frequencies (based on weights constructed to ensure sample representativeness; see Methods) were used.
Table 3:
Sociodemographics and Risk/Benefit Assessment – Research Scenario & Passed Test Questions1
| Risk-Benefit Evaluation | ||||
|---|---|---|---|---|
| Characteristic [N (%)] | Risks probably/definitely outweigh benefits | Risks and benefits equal | Benefits probably/definitely outweigh risks | p value |
| Gender Identity | ||||
| Male | 71 (28.46) | 77 (33.07) | 97 (38.47) | 0.012 |
| Female | 94 (36.99) | 95 (37.51) | 62 (25.50) | |
| Age | ||||
| 18–29 | 23 (27.85) | 30 (39.09) | 29 (33.06) | 0.615 |
| 30–44 | 47 (36.39) | 38 (31.09) | 42 (32.51) | |
| 45–59 | 40 (29.43) | 53 (39.48) | 41 (31.09) | |
| 60+ | 55 (37.54) | 51 (32.32) | 47 (30.14) | |
| Race | ||||
| White | 134 (32.21) | 147 (36.32) | 131 (31.47) | 0.845 |
| Black or African American | 12 (34.90) | 15 (38.54) | 11 (26.56) | |
| Asian | 7 (33.88) | 5 (23.92) | 9 (42.20) | |
| Other | 12 (40.37) | 5 (25.39) | 8 (34.24) | |
| Ethnicity | ||||
| Hispanic | 23 (39.08) | 13 (27.24) | 18 (33.68) | 0.388 |
| Non-Hispanic | 142 (31.81) | 159 (36.80) | 141 (31.38) | |
| Income | ||||
| Less than $49,999 | 43 (33.48) | 48 (41.67) | 32 (24.85) | 0.206 |
| $50,000 – $99,999 | 59 (36.23) | 53 (31.45) | 52 (32.31) | |
| $100,000 or greater | 63 (29.94) | 71 (34.05) | 75 (36.01) | |
| Education | ||||
| Less than high school | 17 (36.37) | 11 (29.10) | 13 (34.53) | 0.718 |
| High school | 38 (30.39) | 49 (41.64) | 35 (27.97) | |
| Some college | 42 (32.27) | 50 (36.96) | 41 (30.78) | |
| Bachelor’s degree or higher | 68 (34.16) | 62 (31.51) | 70 (34.33) | |
| Region | ||||
| Northeast | 33 (34.90) | 37 (36.97) | 25 (28.12) | 0.37 |
| Midwest | 29 (27.45) | 36 (36.74) | 41 (35.81) | |
| South | 68 (38.07) | 61 (34.90) | 48 (27.03) | |
| West | 35 (28.35) | 38 (33.71) | 45 (37.94) | |
| Do you have any children? | ||||
| No | 58 (32.19) | 57 (34.78) | 61 (33.02) | 0.872 |
| Yes | 107 (33.48) | 115 (35.90) | 97 (30.62) | |
| Have any of your children ever had a serious illness? | ||||
| No | 90 (34.33) | 100 (37.80) | 72 (27.88) | 0.0744 |
| Yes | 17 (29.42) | 15 (26.84) | 25 (43.75) | |
| Have you ever enrolled in medical research yourself? | ||||
| No | 151 (33.22) | 155 (35.22) | 145 (31.56) | 0.877 |
| Yes | 14 (29.30) | 17 (37.16) | 14 (33.54) | |
| Have you ever enrolled any of your children in medical research? | ||||
| No | 105 (34.25) | 109 (35.82) | 91 (29.93) | 0.396 |
| Yes | 2 (17.75) | 6 (37.57) | 6 (44.68) | |
| Attitudes Toward Research | ||||
| Medical researchers can be trusted to protect the people who take part in their studies. | ||||
| Disagreed | 38 (46.28) | 26 (35.39) | 14 (18.33) | <0.0001 |
| Neutral | 76 (36.34) | 85 (40.63) | 47 (23.03) | |
| Agreed | 46 (23.21) | 60 (30.95) | 94 (45.84) | |
| People have some responsibility to help others by participating in research. | ||||
| Disagreed | 57 (53.02) | 36 (32.25) | 16 (14.72) | <0.0001 |
| Neutral | 55 (31.45) | 78 (46.10) | 41 (22.45) | |
| Agreed | 48 (22.01) | 57 (28.76) | 98 (49.23) | |
| Medical research is important for helping to improve health and combating disease | ||||
| Disagreed | 2 (35.70) | 0 (0) | 3 (64.30) | N/A |
| Neutral | 13 (44.72) | 15 (54.27) | 1 (1.01) | |
| Agreed | 145 (31.85) | 156 (34.92) | 151 (33.22) | |
Counts unweighted, proportions weighted, p values based on weighted analysis
Respondents who identified as male were significantly more likely to regard the potential medical benefits as outweighing the risks (P = .012). Those who had a positive view of research and researchers (as measured by the three “attitudes toward research questions”) were also significantly more likely to view the potential medical benefits as outweighing the risks (p < 0.0001). Finally, those who reported having had a child with a serious illness may have been more likely to regard the potential medical benefits as outweighing the risks, but this finding did not reach statistical significance (p = 0.0744). No other statistically significant associations were found between the sociodemographic characteristics of the research scenario respondents who passed all three test questions and their risk/benefit evaluations.
Acceptability of Non-medical Reasons for Participating
With respect to studies whose risks were specified as outweighing the potential medical benefits, 59.1% (432/731) of all research scenario respondents believed it could still be appropriate to enroll children for non-medical reasons. Of these 432 respondents, an overwhelming majority (86.1 – 90.9%) approved of all the non-medical reasons presented, except one—“enrolling provides a way for parents to make some money”—which only 10.1% of respondents regarded as appropriate (Table 4).
Table 4:
Appropriateness of Non-medical Reasons to Enroll Child1
| Non-medical Reason2 | All (N = 432)3 | Percent4 | Passed test question (N = 319) | Percent4 |
|---|---|---|---|---|
| Offers a way to help other children with cancer | ||||
| Definitely not appropriate | 7 | 1.9% | 3 | 1.1% |
| Probably not appropriate | 43 | 10.2% | 34 | 10.9% |
| Probably appropriate | 282 | 66.3% | 207 | 65.4% |
| Definitely appropriate | 93 | 21.7% | 72 | 22.6% |
| Missing | 7 | 3 | ||
| Offers a way to continue to fight the disease and maintain hope that the child might get better? | ||||
| Definitely not appropriate | 6 | 1.5% | 4 | 1.5% |
| Probably not appropriate | 44 | 10.4% | 32 | 10.0% |
| Probably appropriate | 276 | 64.7% | 203 | 64.2% |
| Definitely appropriate | 99 | 23.4% | 78 | 24.3% |
| Missing | 7 | 2 | ||
| Participating in research that might help other children provides a way to bring some meaning to a bad situation | ||||
| Definitely not appropriate | 6 | 1.3% | 4 | 1.3% |
| Probably not appropriate | 53 | 12.7% | 41 | 13.3% |
| Probably appropriate | 280 | 66.0% | 208 | 66.2% |
| Definitely appropriate | 87 | 20.1% | 64 | 19.3% |
| Missing | 6 | 2 | ||
| Enrolling provides a way for parents to make some money | ||||
| Definitely not appropriate | 238 | 54.9% | 200 | 62.8% |
| Probably not appropriate | 115 | 26.8% | 85 | 27.1% |
| Probably appropriate | 64 | 16.4% | 28 | 9.2% |
| Definitely appropriate | 8 | 1.9% | 3 | 0.9% |
| Missing | 7 | 3 | ||
| There are no other options | ||||
| Definitely not appropriate | 3 | 0.6% | 1 | 0.3% |
| Probably not appropriate | 32 | 8.5% | 17 | 6.0% |
| Probably appropriate | 251 | 58.8% | 190 | 60.3% |
| Definitely appropriate | 139 | 32.1% | 108 | 33.4% |
| Missing | 7 | 3 |
Counts unweighted, proportions weighted
For verbatim wording of the questions, see supplemental information
Only respondents who indicated that non-medical reasons can generally be appropriate were asked these specific questions
Respondents who did not answer the question (“Missing”) are not included in the percent calculation
Discussion
Assessing whether the potential medical benefits of phase 1 pediatric trials justify the risks is critical to determining whether these trials are ethical and approvable. Absent an algorithm that can be used to draw definitive conclusions, the best way to make this assessment is to consider the views of informed and reasonable individuals. One approach would be to consider the decisions made by parents of children with advanced cancer. The fact that many parents who face these decisions decide to enroll their children might thus be thought to imply that the potential medical benefits do justify the risks. However, the consent process for phase 1 trials might not always results in parents appreciating the high risks and very low prospect of medical benefit. In addition, parents with very sick children may not be in a good position to carefully compare risks and potential medical benefits.
With these concerns in mind, we surveyed a representative sample of the US public who were not experiencing the challenge of a child with advanced cancer. In addition, after explicitly describing the risks and potential medical benefits, we quizzed respondents to ensure they understood them. Our conclusions are based on the subset of respondents who answered all three test questions correctly. The fact that even reasonable and informed individuals can make mistakes implies that the present approach will not settle the debate definitively. But, it likely provides the most reliable estimates available to inform current practice.
We were concerned that respondents might think the risks outweigh the potential medical benefits simply because the treatment was being offered in the research rather than the clinical setting. To assess this possibility, we randomized respondents to a research or clinical care scenario. Our finding that more respondents in the research scenario regarded the potential medical benefits as equal to or outweighing the risks does not support this possibility. Hence, for the purposes of assessing the acceptability and approvability of phase 1 pediatric oncology trials, we focus on the findings from the respondents in the research scenario.
More research will be needed to assess why respondents regarded the treatment as offering a less favorable risk/benefit profile when it was provided in the clinical setting. One possibility is that the wording of the question in the clinical care scenario—“one more possible treatment that you can try” —might have made it sound like there was no evidence to suggest the treatment might be effective. This might have resulted in respondents viewing the possible treatment somewhat less favorably in the clinical care scenario. In contrast, the wording in the research scenario—“enroll your child in a research study that is testing an experimental cancer treatment”—might have avoided this effect by suggesting that the treatment was being tested based on evidence that it might be effective.
A second possibility, suggested by a few studies, is that respondents might have regarded the care provided in clinical trials as superior to the care provided in the clinical setting.[28–30] If we assume, pending further research, that both factors had some influence in the present survey, a better estimate for the percentage of respondents who regard the potential medical benefits as justifying the risks might be 62%−63% (rather than 67%). This difference, we believe, would not alter our analysis or conclusions.
Of the respondents in the research scenario who passed all three test questions indicating they understood the risks and potential medical benefits, approximately one-third regarded the potential medical benefits as outweighing the risks, approximately one-third regarded the potential medical benefits as equal to the risks, and approximately one-third regarded the risks as outweighing the potential medical benefits. These findings have several important implications.
First, the fact that a significant proportion of the US public endorses each of the three possible views helps to explain why there continues to be significant debate over the appropriateness of phase 1 pediatric oncology studies. Second, the fact that two-thirds of respondents who accurately understood the potential medical benefits and risks indicated that the potential medical benefits are equal to or greater than the risks demonstrates that a clear majority of the US public thinks average phase 1 pediatric oncology trials do not pose net risks to participants. This suggests that a clear majority thinks the potential medical benefits justify the risks. In the absence of any treatment alternatives which offer a more favorable risk-benefit profile, then, participation in these trials is not contrary to individuals’ clinical interests.
This finding suggests these trials are not taking advantage of parents who fail to understand the risks and potential medical benefits and enroll their children out of desperation. It also provides reason to think that phase 1 pediatric oncology studies with average or more favorable risk/benefit profiles are ethically appropriate with respect to risks and benefits, and approvable under existing US federal regulations in children who do not have any more favorable treatment alternatives.
Notably, respondents with children who have a history of serious illness trended towards viewing the potential medical benefits as more likely to justify the risks. However, their evaluation was not drastically different than that of the parents of children without a history of serious illness. This suggests that parents who decide to enroll their children in phase 1 pediatric oncology trials are not acting out of desperation due to their circumstances.[31]
Third, although two-thirds of respondents regarded the potential medical benefits as equal to or greater than the risks, a third indicated that the risks outweigh the potential medical benefits. This reveals that a significant minority of individuals consider these trials to be ethically problematic with respect to risks and potential medical benefits. This finding supports a cautious approach, which approves these trials only when they offer significant potential for improving care for children with cancer.
Fourth, even when the only alternative was comfort care, just slightly more than half of respondents considered it appropriate to enroll children in trials with the risk/benefit profile of average phase 1 pediatric oncology trials, and slightly less than half indicated that they would enroll their own child. Future research will be needed to assess why some respondents regarded the described study as posing no net risks, yet still considered it to be inappropriate for children.
Some respondents might consider it ethically problematic to collect data from minors who cannot consent for the benefit of future patients. Others might have been skeptical about whether the research would collect valuable data that might benefit future patients. Alternatively, in the setting of advanced cancer, many parents are likely to prioritize accessing treatments whose potential medical benefits outweigh the risks. These parents might not have been interested in enrolling their child in clinical trials whose risks and potential medical benefits are equal. Moreover, given their focus on accessing beneficial treatment, these parents may consider it inappropriate to conduct trials in children when the risks and potential medical benefits are equal, even when the trial has important social value and there are no more effective options.
In our view, this possibility does not suggest that early phase pediatric trials which have important social value and offer potential medical benefits that are equal to the risks are ethically problematic. However, it does highlight the importance of ensuring that parents are able to make enrollment decisions based on their own preferences and goals. This requires a high-quality informed consent process that accurately educates parents regarding the risks and the potential medical benefits, and how the trial’s risk-benefit profile compares with the risk-benefit profile of available alternatives. Moreover, given the importance of accurate understanding, it might make sense to assess parents’ understanding and permit them to enroll their child only after it has been determined that they accurately understand the risks, potential medical benefits, and alternatives.
Fifth, 59.1% of respondents indicated that it can be appropriate to enroll children for reasons other than a favorable risk/benefit profile. For example, 52% of respondents indicated that it can be appropriate to enroll children in studies that do not offer a favorable risk/benefit ratio because participation offers a way to fight the disease and maintain hope. These data are consistent with previous studies which found that individuals have many reasons for enrolling in phase 1 oncology studies.[32] Moore found that phase 1 studies fulfilled (adult) patients’ “need to try everything in their fight against cancer” and allowed them to maintain hope.[33] Parents have similarly reported that enrolling in research to help children in the future can bring “some meaning” to a bad situation.[34–36]
US regulations direct IRBs to consider only the “direct” benefits when evaluating the risk/benefit profile for participants.[37,38] These non-medical factors thus should not be regarded as sufficient to justify studies when the risk/benefit profile is clearly unfavorable for participants. However, given these other possible motivations, it can be appropriate to default on the side of permitting early phase pediatric trials when it is unclear whether the potential medical benefits justify the risks.
Finally, only about 6% of respondents overall indicated that it can be appropriate to enroll children as a way for parents to make money. This finding supports the prevailing view that making money should not be a reason to enroll children in risky research.[39]
Our estimates of the risks and potential medical benefits of average phase 1 pediatric oncology trials are based on existing data. Our findings thus inherit the limitations of these data. Most importantly, it is currently unclear to what extent surrogate benefits, like tumor shrinkage, translate into clinical ones, such as extended life. The wording of the risks and potential medical benefits in the survey reflected this uncertainty. In addition, we did not assess how sensitive respondents’ views were to the specific risks and potential medical benefits. Hence, our data cannot be used to determine how the US public might view early phase pediatric trials with a risk/benefit profile that is somewhat less favorable than average phase 1 pediatric oncology trials. Finally, the present findings are based on a hypothetical study and included many respondents who are not parents and only a few parents of sick children.
Pediatric clinical trials are ethical and approvable only when they have important social value and do not pose excessive risks. Critics express concern that, by exposing participants to significant risks and offering a very low chance of medical benefit, phase 1 pediatric oncology trials do not satisfy this condition. Instead, they collect data to benefit future patients by taking advantage of parents and children who overestimate the potential medical benefits and/or underestimate the risks. To assess this concern, we evaluated whether a representative and informed sample of the US public considers the potential medical benefits of average phase 1 pediatric oncology trials to justify the risks.
We found that about 1/3 of respondents who accurately understood the risks and potential medical benefits thought the potential medical benefits outweigh the risks, about 1/3 thought the potential medical benefits and risks are equal, and about 1/3 thought the risks outweigh the potential medical benefits. These findings suggest that a significant majority of the US adult population believes that average phase 1 pediatric oncology trials, as well as other early phase pediatric trials with similar or more favorable risk/benefit ratios, do not expose participants to net risks. Absent an alternative with a more favorable risk-benefit profile, participation in these trials is not contrary to participants’ clinical interests, suggesting they are ethically appropriate and approvable.
At the same time, the present findings reveal that a significant minority of individuals think the risks of average phase 1 pediatric oncology trials outweigh the potential medical benefits. Given this concern, these trials should be approved only when they have the potential to gather data that is of significant value in terms of potentially improving care for future patients. Moreover, approximately half of respondents indicated that these trials are inappropriate and they would not enroll their own children. Future research will be needed to assess these findings. They may reflect the fact that many parents of seriously ill children prioritize accessing treatments which offer a favorable, and not just a neutral risk-benefit profile. With this possibility in mind, these trials should include a rigorous informed consent process which accurately educates parents regarding the risks, potential medical benefits, and alternatives so they can make enrollment decisions their children based on their own preferences and goals.
Supplementary Material
Figure 1.
Flowchart of Recruitment and Analysis
Acknowledgements:
We thank the respondents for their participation in our survey, the participants of the NIH Department of Bioethics Empirical Research Laboratory for their helpful comments on the draft survey, and Scott Kim, MD, PhD, NIH, for his suggestions regarding the manuscript. S.K. declares no conflicts of interest.
Funded by the Intramural Research Program at the NIH Clinical Center. The NIH had no role in the study design, the collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the paper for publication. The authors declare no conflicts of interest.
Footnotes
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Contributor Information
Will Schupmann, Department of Bioethics, NIH Clinical Center.
Xiaobai Li, Biostatistics and Clinical Epidemiology Service, NIH Clinical Center.
David Wendler, Department of Bioethics, NIH Clinical Center.
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