Abstract
Background
The National Cancer Institute Cancer Screening Research Network is launching a pilot study (Vanguard) to determine feasibility of successful completion of a clinical trial of multicancer detection tests. This focus group study reports perceptions of primary care physicians and laypersons of different clinical trial designs and willingness to participate in a multicancer detection clinical trial.
Methods
We undertook 14 focus groups with 88 laypersons and 6 focus groups with 45 primary care physicians. Participants were shown graphics of clinical trial designs and asked for their reactions. Focus group recordings were transcribed verbatim, and thematic analysis of the transcripts were conducted to identify emergent themes.
Results
Primary care physician and layperson participants recognized the importance of conducting clinical trials to determine the clinical utility of multicancer detection tests. Primary care physicians expressed reluctance to participate in trials because of workload burden, and laypersons expressed hesitancy about enrolling in the control group. Primary care physicians and laypersons expressed concern about a study design in which multicancer detection test results would not be returned to the control group (intended effect), but they respectively indicated a willingness to refer patients to, or participate in, a multicancer detection test clinical trial given transparent and clear communication on collection and use of biospecimens and data, particularly if a multicancer detection test would eventually be run and results eventually returned.
Conclusion
This study yielded important insights to guide trial design in planning prospective evaluation of multicancer detection testing. Maintaining transparency and trust while possibly withholding multicancer detection test results to maximize trial feasibility and efficiency is of particular concern.
Multicancer detection tests, also referred to as multicancer early detection tests, are blood-based tests intended to screen for multiple cancer types simultaneously (1,2). To date, most investigations of multicancer detection tests have focused on performance validation using banked specimens of individuals with and without cancer (3). The gold standard for demonstrating clinical utility for a specific cancer screening approach involves establishing improvements in cancer-specific endpoints, ideally a reduction in mortality, in randomized controlled trials (RCTs). In considering study designs for large-scale randomized trials, balancing feasibility of successful trial completion with rigor of the desired measurement of outcomes is imperative. Cancer screening trials generally require large sample sizes to power for relatively low frequency endpoint events (particularly related to cancer-specific mortality), take a long time to complete, and are costly (4). Innovative approaches are needed to reduce time and cost without diminishing study rigor or compromising validated endpoints.
Two prospective studies to evaluate multicancer detection test performance have been reported, totaling more than 16 000 participants without known cancer (5). The Pathfinder study (NCT04241796) (6) and the Detecting cancers Earlier Through Elective mutation-based blood Collection and Testing study (7) identified some cancers at early stages that have no recommended screening tests, collectively including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies. Neither study randomly assigned participants to nonscreening arms, and neither had a clinical utility endpoint. Trial results are expected in 2026 from the only prospective RCT to evaluate clinical outcomes of multicancer detection tests. The ongoing NHS-Galleri trial (NCT05611632) has enrolled more than 140 000 participants without known cancer from the general population in the United Kingdom. The trial will employ standard cancer screening in both arms; the intervention arm will also receive multicancer detection testing, and those with a positive result will undergo a diagnostic workup. Blinding is maintained for the other study participants, which is a departure from standard RCT design (8). The only participants who will receive results are those in the intervention arm, and only if positive (9). The primary trial endpoint is a statistically significant reduction in the incidence rate of stage III and IV cancers diagnosed in the intervention arm vs control arm (9). Late-stage cancer incidence can possibly serve as an alternative to cancer mortality for specific cancers, but its association with cancer mortality varies by cancer type (10). A reduction in late-stage incidence (or stage shift) has not been established or validated as a surrogate endpoint for overall cancer mortality in the evaluation of cancer screening interventions.
Although evidence to date supporting their clinical validity and clinical utility is limited, multiple multicancer detection tests are currently being promoted to physicians, health systems, and the public (5,8). The National Cancer Institute (NCI) recently launched Cancer Screening Research Network (CSRN), which was created to systematically evaluate new cancer screening approaches and will begin its activities by assessing the clinical outcomes of multicancer detection tests (11-13). The NCI CSRN will first conduct a pilot study called the Vanguard Study to ascertain the feasibility of random assignment, assess the clinical workflow for the diagnostic pathway, and assess the potential harms and risks of multicancer detection cancer screening, as well as build the infrastructure needed to implement a definitive large-scale RCT to evaluate the impact of population-based multicancer detection testing on cancer mortality (11). Different study designs will be considered to evaluate clinical utility. One potential design is to perform multicancer detection testing in only the intervention group and only returning positive test results. The benefit of returning only positive results is that most participants remain blinded and therefore are likely to continue standard of care cancer screening. Other designs explore timing of multicancer detection testing among the control group (ie, never vs during the trial vs at the end of the trial), with the intent of biobanking specimens, minimizing anticipated control participant regret, and maximizing retention. To maximize timeliness of results, an intended effect analysis (14,15) has been suggested as one study design for the Vanguard Study. The intended effect design would require multicancer detection testing in both the intervention and a selected subset of the control arm. In the control arm, multicancer detection test results would not be disclosed or acted on. This design, in which the control group also receives a multicancer detection test but the results are not known or acted on by participants or their healthcare professionals, would substantially reduce required sample size and/or increase statistical power by comparing rates of the endpoint only for those for whom that endpoint could have been affected by screening.
The acceptability of these various potential trial designs to evaluate multicancer detection testing as a cancer screening intervention is unknown. We therefore conducted formative research aimed at exploring the perceptions and concerns of primary care physicians and laypersons related to potential clinical trial designs and their willingness to participate in a clinical trial for multicancer detection tests.
Methods
Study design
In May-June 2023, we conducted 14 layperson focus groups with 88 participants, including 2 focus groups composed of and moderated by persons who self-identified their race as Black or African American and 2 focus groups for Spanish-speaking participants that were moderated in Spanish. As Black and Hispanic populations make up the largest underrepresented racial and ethnic populations in the United States, these focus groups were performed to ensure that the needs of these populations did not differ greatly from the needs of other populations who might potentially enroll into a large prospective cancer screening trial. In February 2023, we conducted 6 primary care physicians focus groups with 45 participants.
The research protocol (ICF Project Number: 210631.0.001.01.004.01.01) was approved by ICF’s institutional review board (IRB) and determined to be exempt. Written and verbal consent were obtained from participants prior to participation. All participants received a gift card at the end of the focus group ($300 for primary care physicians, $125 for laypersons).
Recruitment
We recruited layperson and primary care physician participants using a national consumer research panel customized by the research firm Sago (16). Sago first identified possible participants in their panel and sent a recruitment e-mail with a screening questionnaire to assess eligibility and interest in participating (Supplementary Materials 1-3, available online). A recruiter called screened participants and confirmed eligibility and availability by phone.
Eligibility criteria for the layperson study consisted of the following: 1) age 50-75 years, 2) English- or Spanish-speaking proficiency, 3) no prior multicancer detection screening test experience, and 4) no cancer diagnosis and/or cancer treatment within the past 5 years. The layperson screening questionnaire also included basic demographic questions, whether potential participants had a previous multicancer detection test, and questions to assess literacy level. Laypersons were recruited into either English-speaking or Spanish-speaking groups depending on their primary language. English-speaking Black participants were recruited to mixed-race groups or groups made up of participants who self-identified as Black or African American to offer the opportunity for transparent and frank expression of potential ethical concerns about the study given historic mistrust in scientific research and underenrollment of Black participants in clinical trials (17,18). Thematic comparisons of coded excerpts between the segmented and heterogenous groups were conducted.
Eligibility criteria for the primary care physician study included 1) US-certified internal or family medicine MD or DO, 2) experience conducting or ordering cancer screening tests, 3) current active clinical practice, and 4) English speaking. The primary care physician screening questionnaire also asked basic demographic questions, questions about their type of medical practice, how long they had been practicing, the main patient population(s) served, and prior knowledge of and experience with multicancer detections.
Sampling and data collection
Focus groups were conducted on QualBoard, a virtual platform that allowed for video and screen sharing. Each group lasted approximately 90 minutes and was video and audio recorded, and a note taker (SC or KD) captured initial concepts that arose. Each group included 4-8 participants and was facilitated by moderators from ICF with either an MPH and/or PhD and a minimum of 10 years of experience conducting qualitative research. The moderators used a semistructured interview guide with open-ended questions and closed-ended probes designed to facilitate discussion (Supplementary Materials 4-6, available online). These guides provided explanations of multicancer detection tests, including potential and limitations as well as mention of the necessity of diagnostic workups following a positive test signal, to the focus group participants. The interview guide was developed by ICF and NCI researchers and refined after piloting with the first focus group.
Clinical trial design descriptions
The study designs presented to the participants (see Table 1; Supplementary Figures 1 and 2, available online) included trade-offs related to disclosure of results vs efficiency of accrual and retention, while maintaining clinical equipoise. The 5 clinical trial designs explored were as follows:
Table 1.
Multicancer detection clinical trial study designs
Design 1. Standard randomized control trial. | |||
---|---|---|---|
Blood draw | Test | Results (all) | |
Control | |||
Intervention | X | X | X |
Design 2. Standard randomized control trial, but control group specimens are biobanked. This leaves open the possibility for testing banked specimens in the future. | |||
---|---|---|---|
Blood draw | Test | Results (all) | |
Control | X | ||
Intervention | X | X | X |
Design 3. By returning only the positive results, participants who do not receive results do not know if they are in the control group or in the intervention group. This may increase retention of control group participants and may also improve standard of care cancer screening compliance. | |||
---|---|---|---|
Blood draw | Test | Results (positive) | |
Control | X | ||
Intervention | X | X | X |
Design 4. Control group receives a multicancer detection test, but the results are only revealed to participant and healthcare professional after the trial. | |||
---|---|---|---|
Blood draw | Test | Results (positive) | |
Control | X | X | X (after trial) |
Intervention | X | X | X |
Design 5. Control group receives a multicancer detection test, but the results are unknown by participant and healthcare professional. | |||
---|---|---|---|
Blood draw | Test | Results (positive) | |
Control | X | X | |
Intervention | X | X | X |
Standard RCT, nonblinded: Blood draw and testing performed, and test results returned only for intervention group.
Standard RCT, blinded: Blood draw performed for all participants, testing performed only for intervention group, and test results returned only to intervention group.
Intended effect trial, intervention group testing, intervention group disclosure: Blood draw performed for all participants, testing performed only for intervention group, and positive test results returned only to intervention group.
Intended effect trial, universal testing, intervention group disclosure, delayed control group disclosure: Blood draw performed for all participants, testing performed for all participants, positive test results returned only to intervention group during the trial, and positive test results returned to control group after the trial.
Intended effect trial, universal testing, intervention group disclosure: Blood draw performed for all participants, testing performed for all participants, and positive results returned only to intervention group.
Focus group participants were shown graphical representations of these clinical trial study designs and asked for their reactions. The primary care physician focus groups were asked about clinical trial designs 1 and 5 (Supplementary Figure 1, available online). For clarity of the differences between the hypothetical trial designs, the layperson focus groups were asked about all 5 designs, with designs 1 and 2 presented verbally and designs 3-5 accompanied by visuals (Supplementary Figure 2, available online).
Data analysis
All focus group recordings were transcribed verbatim by a professional transcription service. The transcripts included the participant’s first name (for tracking purposes) and were only accessible to study staff. After the focus groups were complete, the ICF researchers conducted a systematic, iterative thematic analysis of the transcripts (19): 3 coders (TS, SC, and KD) read through all notes and transcripts and developed an initial codebook based on the moderator guide and initial field notes. They coded one transcript together, compared and revised initial codes, and developed a final working codebook. Next, they used the codebook to individually code the other transcripts line by line, using the qualitative software program NVivo 20. The team met periodically to discuss new concepts that arose and reconcile coding discrepancies or inconsistencies. Once all transcripts were coded, they independently reviewed the excerpts from all codes and identified emergent themes. They met a final time to discuss findings and achieve consensus on the final themes.
Results
Focus group participant demographics
Demographic characteristics of the focus group participants are presented in Table 2. The mean age for primary care physicians was 55.2 years (range = 35-75 years), and for laypersons was 63.9 years (range = 52-74 years). Most primary care physicians were White race (78%) and 20% were Asian race. For the laypersons, 43% were White race, 32% were Black race, and 18% were Hispanic race.
Table 2.
Focus group participant demographics
Primary care physicians, No. (%) (n = 45) | Laypersons, No. (%) (n = 88) | ||
---|---|---|---|
Age, mean (range) | 55.2 (35-75) | Age, mean (range) | 63.9 (52-74) |
Race and ethnicitya | Race and ethnicitya | ||
Asian | 9 (20) | Asian | 3 (3) |
Hispanic or Latino | 2 (4) | Black or African American | 28 (32) |
Non-Hispanic or Latino | 43 (96) | Hispanic or Latino | 16 (18) |
Other | 1 (2) | Multiple | 3 (3) |
White | 35 (78) | White | 38 (43) |
Gender | Gender | ||
Man | 27 (60) | Man | 37 (42) |
Woman | 18 (40) | Woman | 51 (58) |
Geographic region | |||
West | 8 (18) | Neighborhood area | |
South | 11 (24) | Rural | 9 (10) |
Northeast | 13 (29) | Suburban | 50 (57) |
Midwest | 13 (29) | Urban | 29 (33) |
Type of geographic area | Education level | ||
Suburban | 22 (49) | Less than high school | 2 (2) |
Urban | 18 (40) | High school diploma | 28 (32) |
Rural | 5 (11) | Trade school | 6 (7) |
Medical specialty | Bachelor’s degree | 32 (36) | |
Internal medicine | 25 (56) | Master’s Degree | 17 (19) |
Family medicine | 20 (44) | Doctoral Degree or higher | 3 (3) |
Time providing health care | Prefer not to say | 0 (0) | |
≥21 years | 32 (71) | Household income | |
16-20 years | 5 (11) | <$25 000 | 6 (7) |
11-15 years | 4 (9) | $25 000-$49 999 | 17 (19) |
1-10 years | 4 (9) | $50 000-$74 999 | 24 (27) |
Medical practice setting | $75 000-$99 999 | 16 (18) | |
Independent physician-owned practice | 28 (62) | >$100 000 | 18 (20) |
Large medical group, health maintenance organization, or health-care system not associated with a university | 12 (27) | Prefer not to say | 7 (8) |
Academic group practice associated with a university | 3 (7) | Type of insurance | |
Community health center | 1 (2) | Medicare | 39 (44) |
Other clinic or hospital-based practice not associated with a university | 1 (2) | Not specified | 0 (0) |
Patients seen in a week | Private insurance | 43 (49) | |
≥126 | 11 (24) | Uninsured | 6 (7) |
51-75 | 11 (24) | VA health care | 0 (0) |
75-100 | 11 (24) | Immediate family member history cancer | |
101-125 | 6 (13) | Yes | 43 (49) |
25-60 | 6 (13) | No | 45 (51) |
Percentage of uninsured patients,c % | Previous diagnosis of cancer | ||
0 | 6 (13) | Previous diagnosis | 9 (10) |
1-5 | 22 (49) | No previous diagnosis | 79 (90) |
6-10 | 9 (20) | Perceptions of cancer riskb | |
11-20 | 7 (16) | About as likely to get cancer | 33 (38) |
45 | 1 (2) | Less likely to get cancer | 21 (24) |
Percentage of patients insured by Medicaid, % | More likely to get cancer | 18 (20) | |
0 | 3 (7) | I don’t know | 16 (18) |
1-10 | 12 (27) | Previous testing experience | |
11-20 | 13 (29) | Mammogram | 25 (28) |
21-50 | 14 (31) | Pap smear | 23 (26) |
51-100 | 3 (7) | Coloscopy | 26 (30) |
Prostate cancer screening | 13 (15) | ||
Lung cancer screening | 2 (2) | ||
Other | 3 (3) |
Race and ethnicity categories allowed “select all that apply.”
Compared with average person of same age.
Percentages were specified by respondents and then categorized.
Primary care physician focus groups
Multicancer detection clinical trial participation: positive and negative attitudes
Overall, primary care physicians recognized the importance of gathering these data to advance the field and had overall positive attitudes toward participating in a multicancer detection test clinical trial (Table 3, line 1). Primary care physicians also supported this trial because they perceived multicancer detection tests as relatively noninvasive and having minimal impact on patients’ health because trial participants would still receive the standard of care (Table 3, line 2).
Table 3.
Primary care physician focus group quotes
Considerations | Line | Quote | Participant |
---|---|---|---|
Willingness to refer patients to a multicancer detection clinical trial | |||
Importance of gathering clinical data | 1 | “We all have questions how are we going to use this test? How do we follow up on the positives? … So the more we can get data, then the better we’ll be able to utilize this tool more effectively in our practices.” | Man, internal medicine primary care physician with ≥21 years of experience, focus group 2 |
Minimally invasive and low risk of intervention | 2 | “I agree that this is minimal. … This is the sort of study that makes a lot of sense, because it’s not going to harm the patient anyway, and my assumption is … I’m going to treat in parallel to this, so you’re good for your mammogram, you’re good for your colon cancer screening.” | Woman, internal medicine primary care physician with 11-15 years of experience, focus group 4 |
Psychological burden of trial participation | 3 | “Of course, there’s an extensive psychological component that should be included in the screener because we all know how their anxiety really plays a very important role in whatever is coming after that.” | Woman, internal medicine primary care physician with ≥21 years of experience, focus group 3 |
Access burden of trial participation | 4 | “It depends on what requirements would be involved in the study. For example, if it’s going to include PET [positron emission tomography] scanning, our closest PET scan is 350 miles away, so that would definitely be a detriment to doing it.” | Man, family medicine primary care physician with ≥21 years of experience, focus group 3 |
Work burden of patient participation in trial | 5 | “If I order this test, they send the results to me, what do I tell the patient about the results? If I order the test, I have to go over the false positive and the sensitivity with the patient, and I have to spend a lot of time explaining to them what those concepts are, because a lot of patients don’t understand it.” | Man, internal medicine primary care physician with ≥21 years of experience, focus group 3 |
Reactions to nondisclosure multicancer detection clinical trial design | |||
Ethical concerns about nondisclosure of test results | 6 | “I agree that ethics are technically OK, but the optics are awful. I agree, since it’s not proven and they’re still in theory receiving the standard of care in cancer screening, I think it’s technically ethically OK, but it doesn’t feel good.” | Woman, family medicine primary care physician with 16-20 years of experience, focus group 1 |
7 | “Because we enroll the population of the patients with the trust that we are going to let them know if it is positive, we are going to do something about it, and in the second group, even though they are positive in the control group, they will not notify that person, so no workup has been done to assess what the problem is, so that’s a major ethical issue.” | Woman, family medicine primary care physician with ≥21 years of experience, focus group 4 | |
8 | “That’s wrong. You’re holding it and not testing it. We’re playing Russian Roulette and I’m not here to be gambling with people’s lives.” | Woman, internal medicine primary care physician with ≥21 years of experience, focus group 5 | |
Mistrust in health care | 9 | “I think if someone has a positive test and you do not give them that information, and it turns out that it was critically important … there’s no trust in the system anymore.” | Woman, internal medicine primary care physician with ≥21 years of experience, focus group 4 |
10 | “I’m practicing in a population which is mainly African Americans. It’s hard to instill the trust in them, especially if it’s an experimental thing. … I’m pretty sure in my population, they won’t be trusting that.” | Woman, family medicine primary care physician with ≥21 years of experience, focus group 4 | |
Need for transparency and informed consent | 11 | “A lot of times, consent doesn’t mean too much. … I know you’re trying to be transparent, but at the end of the day, if that test comes positive, and if it is not delivered and is on hold for one year, still, it doesn’t make sense. The consent doesn’t mean anything to me.” | Woman, family medicine primary care physician with ≥21 years of experience, focus group 4 |
12 | “I think it would be tough to enroll patients, knowing that they might not get the results, but I think if you put a rider on it and said, listen, at the end of the study, you’ll get a free test regardless, that might make it a little more palatable.” | Man, internal medicine primary care physician with ≥21 years of experience, focus group 6 | |
13 | “I think we all struggle a little bit with the whole concept, but I think again as long as the patients know or the participants know ahead of time that this is the way the trial is set up and they obviously sign a waiver, I just think it might be a little harder sell for me to get one of my patients to enroll in that particular study design because of the way it’s set up.” | Man, internal medicine primary care physician with ≥21 years of experience, focus group 2 | |
Trial efficiency is inadequate justification for nondisclosure | 14 | “These long-term prospective studies, they’re very, very helpful, very informative. … The prospective study that has this type, even they take 20, 30, 15 years, they’re still more helpful than the [nondisclosure design].” | Woman, internal medicine primary care physician with ≥21 years of experience, focus group 6 |
15 | “You don’t have to rush to get results to get a good answer. If it’s a longer study and more acceptable, you got to bite the bullet and stick it out.” | Man, internal medicine primary care physician with ≥21 years of experience, focus group 6 | |
16 | “It takes time to have these things play out. You don’t want to be rushed and then find out that wasn’t the right answer.” | Man, internal medicine primary care physician with ≥21 years of experience, focus group 6 | |
17 | “That’s it. If the IRB [institutional review board] signed off on it, I’d have a lot less heartburn with the [nondisclosure design], but I would be willing to send people to the study as long as they got read the riot act, so to speak, about what they’re going to get out of it and do it beforehand. As long as they knew the rules of the game before we started the game. If they signed up for it, it’s up to them, and it’s beyond my control, and if they’re trying to get this out quicker and the patients are up for that, I don’t have a problem with that as long as they get read the official way that this is going to go down.” | Man, family medicine primary care physician with ≥21 years of experience, focus group 6 | |
Fear of malpractice litigation | 18 | “That’s risky business in this litigious society. The history of human testing is strewn with unethical protocols. … This is a very dicey thing and very precarious for the clinician to suggest this. You have to have such an extremely careful explanation to the patient to understand that if a control group and there’s something that’s positive and they’re not told, this may jeopardize their health. It’s a real serious problem.” | Man, family medicine primary care physician with ≥21 years of experience, focus group 2 |
19 | “It has to be very clearly done because the attorney representing a patient down the road will not just go after the individual doctor, but of course, also go after the trial designers. You have a real fine line here on the ethical, how you try to massage the protocol on it so you can finish it faster, complete it quicker.” | Man, family medicine primary care physician with ≥21 years of experience, focus group 2 | |
20 | “Even if they read it, a good lawyer is going to tear that apart anyway … you had a knowledge of something that could have a major impact in somebody’s health, and you did not disclose it, and … even if it’s a really good test, nobody’s going to be wanting to do it. There’ll be no trust. …You do realize that when you do that, all those people that are positive, they’ll be pissed and sue you?” | Woman, internal medicine primary care physician with ≥21 years of experience, focus group 4 | |
False reassurance from lack of test results | 21 | “Do patients realize that if they don’t hear anything, doesn’t that mean that’s because they fell in the negative group? I would think most people who enroll in this study, it’s because they’re hoping that they’ll get an earlier diagnosis, for free. I think that gives people a false sense of security, and I don’t know how many of them, just because you tell them you need to still continue to do everything you’re supposed to be doing, they will.” | Woman, internal medicine primary care physician with ≥21 years of experience, focus group 3 |
Some primary care physicians said that they would be reluctant to enroll certain patients, such as those with anxiety, given the potential added emotional burden of joining a clinical trial (Table 3, line 3). They also raised issues related to follow-up of abnormal tests, specifically, limited access to needed follow-up care (Table 3, line 4). Some primary care physicians were concerned about undue burden on their clinical practice if they enrolled patients to the multicancer detection clinical trial. Even if the study was separate from their clinical practice (eg, recruitment and study procedures conducted elsewhere) and their patients were referred to the clinical trial, they brought up possible downstream effects, including the need to conduct extra tests and to spend additional time discussing test results (Table 3, line 5).
Despite these concerns, almost all participants reported a willingness to refer patients to a multicancer detection test clinical trial, if safeguards were in place to reduce burden on their clinical practice (ie, if recruitment, enrollment, and follow-up were conducted elsewhere).
Attitudes toward intended effect clinical trial designs involving nondisclosure
Primary care physicians generally had positive attitudes toward participating in a multicancer detection test clinical trial, however, they had negative attitudes toward particular designs, especially study design 5 (Table 1; Supplementary Figure 1, available online), which would perform multicancer detection testing in the control arm but not return the results. These negative attitudes toward the intended effect design persisted despite a perception of clinical equipoise regarding the benefits and harms of multicancer detection testing (Table 3, lines 6-8). Primary care physicians expressed concern that withholding this information could potentially deprive someone of beneficial treatment and result in profound mistrust (Table 3, lines 9-10). One primary care physician reported that presenting the intended effect trial design to her Black patients would discourage them from participating because of their historical mistrust of government-sponsored research due to past injustices (Table 3, line 10).
When presented with the methodological advantages of a nondisclosure/intended effect study design (smaller sample size, faster trial completion), many primary care physicians remained concerned about transparency issues in study design, informed consent, and data collection. Many primary care physicians did not trust the consent process to adequately communicate study risks, benefits, and alternatives (Table 3, line 11). Some primary care physicians worried that patients may be more reluctant to enroll into a study in which some multicancer detection results would be withheld from them (Table 3, lines 12-13). They understood and expected that this population screening research could take years to complete and said that an ethical design approach needed to be the highest concern for researchers (Table 3, lines 14-16). Despite unease around this design, however, many primary care physicians suggested that with IRB approval and transparency in the informed consent process, they would be willing to refer participants to a study with an intended effect design (Table 3, line 17).
Some primary care physicians expressed concern that study researchers would be held liable for the nondisclosure of results if a patient in the control group who did not receive positive results was later diagnosed with cancer, even with legal safeguards in place (Table 3, lines 18-20). Although most of the discussion focused on the trial design involving nondisclosure of positive results (design 5), the primary care physicians also were specifically queried on their thoughts about negative test results not being disclosed in general (Table 1, designs 3-5). Some primary care physicians did not have ethical concerns with nondisclosure of negative results per se but wondered how or if it would affect study participants’ speculation about which arm of the study they had been randomly assigned, because only a small group of study participants (who tested positive in the intervention group) would have any results disclosed. They also perceived that most study participants would assume they were negative if they received no results at all, which might provide false reassurance—although when probed further, they understood that even if participants were informed about negative results, they might also derive the same false reassurance (Table 3, line 21).
Layperson focus groups
Multicancer detection clinical trial participation: positive and negative attitudes
The majority of layperson focus group participants said they would be willing to join a trial if the process was transparent and did not involve too much time or resources. The main motivations for participation included altruism, the relatively noninvasive nature of the intervention, family or personal health concerns that made them want more information about their own health, and the possibility of study incentives (Table 4, lines 1-2).
Table 4.
Laypersons focus group quotes
Theme | Line | Quote | Participant |
---|---|---|---|
Willingness to participate in a multicancer detection clinical trial | |||
Altruism for participation | 1 | “I don’t really have an issue with it because when I joined clinical studies it’s to possibly help me but in the main scheme of things, it’s to help future people. And if I can help in research, it’s just a small part that I can do.” | Woman, age 66 years, White, focus group 9 |
Low risk for participation | 2 | “All they’re doing is taking a little blood from you and running some tests. So there’s very little room for harm to a participant. So for me, I’d do it. It’s nothing to lose. And you could be part of helping a much larger cause.” | Man, aged 56 years, American Indian or Alaska Native and Black or African American, focus group 6 |
Need for transparency during consent | 3 | “For me, I would need to know what the next step is going to be and what the endurance for that next step would be. Is that going to three months, or six months, or a lifetime? I would need to know all of that up front before I agree one way or the other.” | Woman, aged 63 years, Black or African American, focus group 12 (Black or African American group) |
Reluctance to participate in trials | 4 | “In all actuality, I’ve received requests for clinical tests and I’ve never been a willing participant.” | Man, aged 74 years, Black or African American, focus group 12 (Black or African American group) |
5 | “Them doing those kind of trials is a good thing, but I wouldn’t want to be a part of it. I would still want to … see what kind of data comes out of that.” | Woman, aged 60 years, Black or African American, focus group 13 (Black or African American group) | |
6 | “As a person of color, took a lot of time for me to trust doctors in the first place, especially once I learned about what that experiment back in the day after World War II with these Black men, I was skeptical of going to doctors after that for quite a long time until it was explained to me, as I got older I’m more susceptible to a lot of illnesses and I need to see a doctor more often.” | Man, aged 70 years, Black or African American, focus group 9 | |
Skepticism related to interventions | 7 | “The first thing I would ask is, what are the risks am I going to have when a do these tests?” | Woman, aged 65 years, Hispanic or Latino, focus group 14 (Spanish-language) |
8 | “So, this is a new test, so it hasn’t been proven? There’s no data on it, so it’s not reliable?” | Man, aged 67 years, Black or African American, focus group 13 (Black or African American group) | |
Reactions to multicancer detection clinical trial designs | |||
Ethical concerns related to being in control group | 9 | “Why would there be a control group for this? There’s a difference in terms of … how you’re going to report on one way or the other when you’re giving blood. So to me, give everybody the test. I understand the concept of a control group but it doesn’t seem effective in this particular model.” | Man, aged 66 years, White, focus group 1 |
10 | “But at the same time, it’s a little confusing because what if you’re in the control group, thinking, ‘oh, I don’t have anything. They didn’t call me.’ But actually, they never even tested you.” | Woman, aged 55 years, Hispanic, focus group 5 (Spanish language) | |
11 | “It’s like a lottery. Either you win the lottery, or you don’t. If you want to take a chance and you could have these tests, you’re in the lottery. You could be chosen or you won’t be. Although it’s sad for the control group who weren’t selected, that they’re going to follow them and heaven forbid have cancer and potentially die from something when they could have been detected earlier.” | Woman, aged 54 years, White, focus group 11 | |
Concerns about nondisclosure of test results | 12 | “If they’re taking the test, if they’re administering a test, whether it be a control group or whatever, if they come back with something positive, I feel that they should let you know, period.” | Woman, aged 54 years, Black or African American, focus group 12 (Black or African American group) |
13 | “That’s the problem. Because I thought that everyone was notified. I thought if you tested positive, you were going to be notified. But not everyone. We’re not going to know. That makes it a little complicated there, for me.” | Woman, aged 21 years, Hispanic or Latino, focus group 5 (Spanish language) | |
14 | “When you do a study, you want people to feel comfortable. I know money is the center but this is not making people feel comfortable.” | Man, aged 63 years, Black or African American, focus group 12 | |
15 | “There is a finding that is positive, that my health is going to be impeded. And that that finding is locked away under lock and key and that I don’t know. Morally, health professionals know something of a particular person. … That to me in a way is like your doctor having a finding and not sharing it with you.” | Woman, aged 61 years, Black or African American, focus group 2 | |
Standard of care | 16 | “If I had a history of cancer in my family, I would still continue on no matter whether I was in the control group or whatever and I didn’t get an answer from this test. I would still continue on with doing what I normally do. … If I didn’t hear anything, I would just go with my yearly like I’m doing and not do anything about it even though there’s a chance it could have be positive, but it came out negative. I would still do it. Absolutely.” | Woman, aged 65 years, White, focus group 7 |
17 | “It takes that piece out of it because then you sign up for this study and you control doing your own independent testing of your body for cancer. So you really didn’t lose anything in that aspect. You tried something that could give you a head start on finding out about your cancer status, but you never get that information at all, and it’s something that would have been disclosed to you at the beginning of the study. So you kind of knew what you signed up for, per se.” | Man, aged 56 years, American Indian or Alaska Native and Black or African American, focus group 6 | |
Testing after trial completion in the control group | 18 | “The only thing I would want on that is that they would tell me at some point the testing was done. So you wouldn’t sit there and think nothing of it, and then a year later someone sends you a call that you tested positive. So I would like to know that even if I didn’t know which group I was in, just say hey, we concluded our testing.” | Man, aged 62 years, White, focus group 2 |
19 | “I like this one better. … Because at least my blood is going to be tested at some point.” | Woman, aged 56 years, White, focus group 9 | |
20 | “If I was in a control group and my blood was not tested until after the study, I want to know the test results, positive or negative. I don’t care if it was tested during the study. But after the study, it’s tested, then I want to know either way. … I think it just finalizes just from one bookend to the other. It’s over. I’m done. This is what occurred, and this is what the result is, period.” | Woman, aged 61 years, Black or African American, focus group 2 | |
23 | “I like this a lot better also because I’m going to get it tested eventually. And if there’s anything there, I would like to know.” | Man, aged 70 years, Black or African American, focus group 9 | |
Enthusiasm about multicancer detection testing following trial | 24 | “I think for me, … if I was in a control group and my blood was not tested until after the study, I want to know the test results, positive or negative. I don’t care if it was tested during the study. But after the study, it’s tested, then I want to know either way.” | Woman, aged 61 years, Black or African American, focus group 2 |
25 | “I think that would be a great incentive at the end if you were in that control group and they studied you later to give you another test if you wanted it at the end of the study to see where you were again. That’s a great idea. That’s a win-win.” | Woman, aged 60 years, White, focus group 3 |
Although most laypersons had positive attitudes toward clinical trial participation, they also expressed concerns. Participants mentioned wanting details on the study procedures and expectations to be clearly communicated. Another concern related to the amount of time and effort involved in participating (Table 4, line 3).
Although participants in all groups expressed positive and negative attitudes, more negative attitudes were voiced in Spanish-speaking and Black focus groups. Some Black focus group participants said that their lack of prior participation in clinical trials was by choice (Table 4, lines 4-5). Although Black focus group participants did not explicitly specify their reasons for avoiding clinical trial participation, a majority spontaneously brought up race in conversations about unethical medical practices (Table 4, lines 6). Participants in the Spanish-speaking and Black focus groups more often expressed skepticism related to test accuracy, risks, and lack of research transparency than participants in other groups (Table 4, lines 7-8).
Attitudes toward intended effect clinical trial designs involving nondisclosure
When laypersons were presented with possible study designs for a multicancer detection clinical trial (Supplementary Figure 2, available online), a prominent and consistent theme was difficulty for participants to understand the RCT study design (Table 4, lines 9-10), especially the need for a comparison group that would not receive multicancer detection test results. Some participants referred to being randomly assigned into the control group as a loss (Table 4, line 11) even though it was explained to them that the multicancer detection test was experimental and without demonstrated benefit. They unanimously thought that assignment to the intervention group was desirable, even while acknowledging potential harms like undue stress, anxiety, or other adverse effects of the diagnostic workup for a positive multicancer detection test.
When presented with the potential nondisclosure/intended effect study designs in which trial participants in the control group would have their blood tested but would not receive test results (design 5; Table 1, Supplementary Figure 2, available online), participants expressed ethical concerns with this design (Table 4, line 12). Even after acknowledging possible adverse outcomes of false-positive results, some participants expressed hesitancy about participation and lack of understanding of the rationale for this design (Table 4, line 13). For these participants, withholding health information by researchers indicated that clinical trial goals were prioritized over participants’ personal well-being, which they felt violated ethical principles (Table 4, lines 14-15).
A smaller group of laypersons expressed minimal ethical concerns with nondisclosure given that everyone would still get standard-of-care cancer screening; these participants seemed to understand that nondisclosure is often part of research. These participants indicated a willingness to join the clinical trial because they believed that they would not be harmed by nondisclosure of results and would receive conventional cancer screenings (Table 4, lines 16-17).
The strongest preference for study design among laypersons was design 4, which entailed the collection of blood in the control group and delayed testing and result disclosure after completion of the clinical trial (Table 1; Supplementary Figure 1, available online). Overall, participants felt better about this design given that their blood would be tested at some point and results communicated. These participants did not seem to mind that the results would be outdated and possibly several years old; they still wanted their blood to be tested eventually. They also shared that they felt entitled to their health information, even if delayed (Table 4, lines 18-23).
In closing out the focus group discussions, laypersons were asked about whether there were incentives such as receiving health information that would make it worthwhile to participate in a clinical trial of multicancer detection tests (Supplementary Materials 5, available online). Almost all participants were enthusiastic about the option of their blood being tested by a multicancer detection assay after the study completion (Table 4, lines 24-25).
Discussion
This study examined primary care physicians’ and laypersons’ attitudes toward alternative study designs to assess the effectiveness of multicancer detection testing and yielded important insights to guide design of a future clinical trial. Primary care physicians indicated that with transparency in the study documents and full IRB approval, they would be willing to refer patients to this type of trial. Similarly, most laypersons, including participants from historically underrepresented racial and ethnic populations, indicated a willingness to join a multicancer detection test trial if the process was transparent and did not involve too much person time or resources.
Despite an overall willingness to participate, most primary care physicians and laypersons expressed negative attitudes toward nondisclosure of positive results in the control group. Both groups expressed concerns that this design has the potential to deprive a patient of early treatment and to increase mistrust in the healthcare providers and clinical research. Laypersons further expressed the belief that it was more desirable to be assigned to the intervention group. Together, these findings suggest that primary care physicians and laypersons have inflated expectations of the benefits of multicancer detection testing and that such expectations could be a barrier to clinical trial participation. From a strictly scientific standpoint, there is currently equipoise about the net value of multicancer detection testing; this equipoise is the fundamental motivation for future clinical trials. Equipoise ethically justifies the proposed intended effect design, which should not produce more or less harm to control group participants (15). Our findings suggest, however, that primary care physicians and laypersons are skeptical of this equipoise and that increasing participation in multicancer detection clinical trials—regardless of the study design—will require greater efforts to educate both parties about the extent of existing scientific uncertainties about the benefits of multicancer detection testing, the existence of potential harms that warrant consideration but are often disregarded, and the true need for high-quality evidence to reduce these uncertainties. These efforts are all the more necessary and challenging given the extent to which for-profit multicancer detection test manufacturers are marketing multicancer detection testing to physicians and the general public.
Although primary care physicians were generally enthusiastic about enrolling their patients in a multicancer detection clinical trial, their main considerations apart from the trial design involved work burden for themselves in terms of follow-up of a positive multicancer detection test, concern for burden for their patients (both psychological and access to follow-up testing), and concern about medical liability. Our findings support a previous survey in 27 primary care physicians from 4 primary care practices from a large urban health system, which indicated that primary care physicians were concerned about the management of patients who would receive a positive multicancer detection test signal and those who would eventually be diagnosed with cancer in a multicancer detection trial (20). These concerns about clinical management of patients indicate a critical need for standardized approaches to diagnostic follow-up to confirm a positive multicancer detection test that provide clear and concise management guidance to primary care physicians and their patients (21). A potential benefit of a large, prospective trial of multicancer detection testing is the potential for the collection of information about best practices in the diagnostic workup following a positive multicancer detection test.
Laypersons strongly preferred the proposed trial design that collected blood in the control group and performed testing after the trial was completed, rather than testing in real time and withholding results, even though this design would entail storage of blood collections and delay return of results possibly to a time when they would no longer be actionable. This preference is consistent with a widely held preference for disclosure of results among clinical trial participants (22-24). However, our findings shed additional light on specific compromises that participants might be willing to accept if full disclosure of multicancer detection test results could not be offered for justifiable reasons (eg, concerns about validity or usefulness of results or the potential cost, inconvenience, or time burdens on researchers and participants) (24,25). For example, a return of value approach proposed in other research studies allows participants to receive other health information perceived to be of value to them, whether or not it is directly related to the research study they are enrolled in (23,24). One proposed alternative approach in our study is to provide free multicancer detection testing after the trial is complete; several participants viewed this as a positive incentive to join a multicancer detection clinical trial.
Another important study finding is related to the potential influence of medical mistrust on trial participation for participants from historically underrepresented communities. Inclusion of diverse participants in clinical trials is essential to ensuring generalizability of results and feasibility of implementation of research findings (26). Yet despite federal policy and efforts to increase representation of populations historically underrepresented in biomedical research, Black and Hispanic patients remain underaccrued to cancer clinical trials (27,28). A major strength of our study was the inclusion of focus groups for Spanish-speaking and Black participants, which revealed potentially greater medical mistrust among participants in these groups. This finding suggests an important direction for future research and work to improve participation in multicancer detection clinical trials, given that medical mistrust is a commonly cited reason for underrepresentation of minority communities in clinical research (26,29). Future studies should also explore how medical mistrust, race, ethnicity, and other characteristics of physicians may influence their research participation and use of multicancer detection tests—an important research question that was beyond the scope and resources of the current exploratory study.
A related question raised by our study is how medical mistrust might be affected by aspects of a multicancer detection trial, including its study design or the way it carried out. Together, our findings suggest that maintaining trust may pose unique challenges when the study design involves nondisclosure of results from participants, even if such a trial design can be ethically justified by the existence of clinical equipoise. Public and physician attitudes wary of such a design may be driven by beliefs in the positive value of multicancer detection testing or the inherent value of medical knowledge or technology. Such beliefs may predispose laypersons and physicians to judge the prospect of withholding multicancer detection results as unacceptable and may accentuate these effects among members of underrepresented communities, making alternative clinical trial designs to study the effectiveness of multicancer detection testing more challenging to implement. Overall, these findings provide evidence that timely accrual of a diverse, nationally representative patient population into a federally funded clinical trial of multicancer detection tests is feasible. The NCI CSRN plans to integrate insights gained from these focus groups into the development of the Vanguard Study protocol, as well as the consent form and recruitment materials. Special efforts will, however, be required to overcome inflated expectations of the benefits of multicancer detection testing, to educate participants on the extent of scientific uncertainty about the true benefits and harms of multicancer detection testing and to assure transparency and integrity of study procedures.
Supplementary Material
Acknowledgements
The funding source (NCI) undertook the study design, writing of the manuscript, and the decision to submit the manuscript for publication. ICF conducted the study, collected the data, and performed data analysis and interpretation.
The authors are grateful to the focus group participants for their time and insights. We thank Liz Freedman, MPH, NCI DCP, for her input and editing of this manuscript.
Contributor Information
Goli Samimi, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Sarah M Temkin, Office of Research on Women’s Health, National Institutes of Health, Bethesda, MD, USA.
Carol J Weil, Human Research Protections and Bioethics, Independent Consultant, Bethesda, MD, USA.
Paul K Han, Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
Elyse LeeVan, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Wendy S Rubinstein, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Tessa Swigart, ICF Next, Fairfax, VA, USA.
Sarah Caban, ICF Next, Fairfax, VA, USA.
Katherine Dent, ICF Next, Fairfax, VA, USA.
Lori M Minasian, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD, USA.
Data availability
All data are available in the manuscript or supplementary materials or by e-mail request.
Author contributions
Goli Samimi, PhD, MPH (Conceptualization; Investigation; Methodology; Supervision; Writing—original draft; Writing—review & editing), Sarah M. Temkin, MD (Conceptualization; Investigation; Writing—original draft; Writing—review & editing), Carol J. Weil, JD (Conceptualization; Investigation; Writing—original draft; Writing—review & editing), Paul K.J. Han, MD, MA, MPH (Conceptualization; Investigation; Writing—original draft; Writing—review & editing), Elyse LeeVan, MD, MPH(Conceptualization; Investigation; Writing—original draft; Writing—review & editing), Wendy S. Rubinstein, MD, PhD(Conceptualization; Investigation; Writing—original draft; Writing—review & editing), Tessa Swigart, PhD, MS(Data curation; Formal analysis; Methodology; Writing—original draft; Writing—review & editing), Sarah Caban, MA(Data curation; Formal analysis; Methodology; Writing—original draft; Writing—review & editing), Katherine Dent, MPH, MCHES(Data curation; Formal analysis; Methodology; Writing—original draft; Writing—review & editing), and Lori M. Minasian, MD(Conceptualization; Investigation; Project administration; Supervision; Writing—original draft; Writing—review & editing).
Funding
This work was supported by Contract No. GS-00F-010CA, Contract No. 75N91021A00002, Task Order No. 75N91021F00001 from the National Cancer Institute to ICF Next.
Conflicts of interest
TMS, KD, and SC received other funds (contract) from the National Cancer Institute for this work. CJW received personal fees (consultant) from the National Cancer Institute for this work. GS, SMT, PKJH, WSR, EL, and LMM declare no Conflicts of Interest.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data are available in the manuscript or supplementary materials or by e-mail request.