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Colorectal cancer survivors’ willingness to participate in a hypothetical clinical trial of Korean medicine: A cross-sectional study
European Journal of Integrative Medicine 33 (2020) 101033
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Research paper
Colorectal cancer survivors’ willingness to participate in a hypothetical clinical trial of Korean medicine: A cross-sectional study
T
Yown Hwangboa, Gyung Mo Sonb, Kyung Hee Kimb, Myeong Sook Kwonb, Kun Hyung Kima,c,* a
School of Korean Medicine, Pusan National University, Republic of Korea Department of Surgery, Pusan National University Yangsan Hospital, Republic of Korea c Department of Korean Medicine, Pusan National University Hospital, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Willingness to participate Korean medicine Clinical trial Colorectal cancer Cross-sectional survey
Introduction: Growing interest in the role of Korean medicine for cancer survivors has prompted the need for clinical trials to guide its rationale use. The study aimed to identify survivors’ willingness to participate (WTP) in a hypothetical clinical trial of Korean medicine and explore associated factors. Methods: Patients were approached to take part in a cross sectional study. Inclusion criteria were; having undergone colorectal cancer surgery (at least 6 months previously) and attending the outpatient clinic of a tertiary hospital. Multivariate logistic regression was performed to investigate factors associated with WTP using a forward selection method. Results: Of 458 patients screened, 300 participated in the survey. Thirty-two percent of participants expressed WTP in a given trial. Multivariate logistic regression analysis (n = 300) demonstrated that WTP was significantly associated with age of 55–64 years (adjusted OR: 3.33; 95 % CI: 1.34–8.26) and 65–74 years (2.66, 1.07–6.61), past experience of participation in a trial of Korean medicine (5.65, 1.44–22.14), perceived understanding about clinical trials (3.10, 1.20–7.96), altruism to benefit future cancer patients (2.40, 1.33–4.32) and expectation for an improved health condition by trial participation (2.93, 1.61–5.35). Conclusions: One-third (32 %) of colorectal cancer survivors showed WTP in a future clinical trial of Korean medicine. Further studies regarding WTP should be conducted in various contexts to inform the design of Korean medicine clinical trials.
1. Introduction Colorectal cancer survivors suffer from various chronic conditions, such as pain, depressive mood, fatigue and other non-specific symptoms [1]. The use of traditional medicine in the cancer care setting is becoming more popular [2–4], although evidence for or against the use of traditional medicine remains inconclusive in most circumstances. Therefore, well-designed comparative studies, especially fully powered high-quality randomised trials, are warranted to address the current evidence-practice gap. The feasibility of conducting trials largely relies on successful participant recruitment and the completion of data acquisition without significant attrition through the entire study process. Identifying willingness to participate (WTP) and associated facilitating factors and barriers is a key process to enhance recruitment and retention feasibility and inform the design of future trials. In previous
literature, the proportion of participants with WTP in various real or hypothetical trials ranged from 11.1% to 88.3 %, and the associated sociodemographic and clinical factors varied between trials, possibly attributable to the difference of the context, population of interest and the research designs [1]. Such large heterogeneity may imply limited generalizability and context-specific characteristics of previous findings and justify further investigation of WTP and associated factors in different settings. WTP and associated factors in randomised trials of acupuncture have been investigated in the USA in women with breast cancer, showing that almost half of the survey respondents expressed WTP but there were variations in barriers among subgroups [5]. In South Korea, WTP of cancer patients in the context of Western medicine trials has been investigated [6]. However, little is known about WTP in clinical trials of Korean medicine for colorectal cancer survivors. Given the
Abbreviations: WTP, willingness to participate; EMR, the electronic medical records; N, number; SD, standard deviation; IQR, inter quartile range; uOR, unadjusted odds ratio; aOR, adjusted odds ratio; O.R., odds ratio; C.I., confidence interval; NA, not applicable ⁎ Corresponding author at: Department of Korean Medicine, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea. E-mail address: [email protected] (K.H. Kim). https://doi.org/10.1016/j.eujim.2019.101033 Received 20 October 2019; Received in revised form 7 December 2019; Accepted 7 December 2019 1876-3820/ © 2019 Elsevier GmbH. All rights reserved.
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different population characteristics and clinical settings, those findings may not be applicable to colorectal cancer survivors who consider participation in a trial of Korean medicine. Considering the growing interest in evidence-based Korean medicine to address the increasing burden of colorectal cancer survivors, the investigation of WTP and associated factors that can inform future well-designed trial is warranted.
clinical trial for a primary question would be adequate given the assumed baseline lay understanding about clinical trials by participants. To identify WTP in a randomised trial, information on the hypothetical parallel randomised trial of Korean medicine with a simple study flowchart was provided (Appendix 11). We did not specify a particular type of Korean medicine intervention in the information because our aim was to clarify the WTP and associated factors for Korean medicine in general. The particular type of control group intervention, such as placebo or active comparators, were also not specified because we hypothesised that participation in a clinical trial may depend on a type of control intervention. Therefore, the general term “control group intervention” was used. The full translated survey questionnaire is available in Appendix 1. Participants were asked to complete the questionnaire with the help of the trained research assistant in a face-to-face manner or independently as preferred. The expected time to complete the survey was 10−20 min, based on the pilot test. Some clinical characteristics that were obtainable in the electronic medical records (EMR) were not completed by the participants and were extracted from the EMR by the trained nurse and research assistant to avoid recall bias and save time for the survey.
1.1. Study objectives This study aimed to investigate WTP in a hypothetical clinical trial of Korean medicine and its associated factors in colorectal cancer survivors. 2. Methods 2.1. Study design and participants This study was a cross-sectional face-to-face survey of colorectal cancer survivors who had previously undergone surgical resection of cancer at the Pusan National University Yangsan Hospital, a tertiary medical centre covering both urban and rural areas in Gyeong Sang South Province. Yangsan city had a population of 320,400 in February 2017 [7]. Three hundred participants were recruited from February 2017 to June 2017. The inclusion criteria were colorectal cancer patients aged 19 years and older who had undergone surgical cancer resection at least six months ago. Those who were younger than 19 years, had cognitive impairment or physical inability, were unable to complete the survey independently or were under assistance were not eligible. Patients with metastatic cancer or those who were on chemotherapy or radiation therapy were also excluded.
2.4. Re-categorisation of continuous and categorical variables Some of the continuous data were categorised based on the arbitrary cut-off values pre-defined by authors. The primary outcome, WTP, was converted into dichotomous variables (having no WTP as a 0–5 score and having WTP as a 6–10 score). We assumed that common threshold (i.e., 6 points or more on a 0–10 scale) of classifying severe cases of symptoms such as pain would be useful for identifying participants who have WTP. Where considered appropriate, other variables were also converted into simpler categorical variables to avoid too few counts and perform meaningful analyses (Appendix 12).
2.2. Recruitment 2.5. Study ethics A registered nurse screened a list of potentially eligible participants in an outpatient department of the study hospital. In the outpatient clinic room, the study surgeon (GMS) asked the patients to respond to the survey. For patients who agreed to participate in the survey, information on the purpose of the survey was explained by the trained research assistants.
This study was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (PNUYH IRB No.: 04-2017-003). The study was carried out in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
2.3. Survey questionnaire
2.6. Sample size calculation for the cross-sectional study
We developed the study questionnaire based on the review of existing literature investigating factors associated with WTP in various clinical trial settings [1]. A group of investigators including a Korean medical doctor (KHK), a colorectal surgeon (GMS), a surgical nurse and research assistants revised the draft questionnaire. A pilot test was conducted to check the readability and logistics of the questionnaire items in the patients’ perspective and the feasibility of conducting the survey in the outpatient settings. A final version of the survey questionnaire was developed after reflecting the findings from the pilot test. The questionnaire comprised 37 items that covered sociodemographic and clinical characteristics of the participants as well as the participant’s knowledge and perception on participating in a clinical trial of Korean medicine. To identify WTP in clinical trials of Korean medicine, we used the term ‘clinical trial’ as ‘trial that compares the experimental intervention with the control intervention to measure the difference of the clinical outcome, regardless of allocation methods (random allocation, nonrandom allocation or quasi-random allocation)’. Our experience of screening participants in clinical trial of Korean medicine has revealed difficulty of discerning non-randomised and randomised trial by the participants unless further explanation for the allocation scheme was provided. Therefore, we considered that more general description of
Previous literature has shown WTP in a clinical trial is widely distributed from 20 % [8] and 60 % [9], depending on the design, settings and contexts of the investigation. We assumed that the expected proportion of colorectal cancer survivors who may have WTP in the population would be 20 %. The rationale of this assumption is that there have been a few clinical trials of Korean medicine for colorectal cancer patients; thus, relevant information on trials of Korean medicine may not be familiar to them, possibly justifying our assumption on a lower proportion of patients with WTP than those identified in the clinical trial of Western medicine intervention. The α-value for type I error was 0.05. The sample size calculation yielded 246 participants to be investigated to estimate WTP in the population. Considering the possibility of missing answers or logical errors of the answer in 20 % of survey responders, we regarded 300 participants as the required number of subjects in the cross-sectional survey (246 × 1.2 = 295.2 ≒ 300). Formula for sample size calculation is on Appendix 2. 2.7. Development of the multivariable logistic regression model We used a forward selection method to develop the multivariable logistic regression model that explores factors associated with WTP. Age, gender, level of education, employment status and level of income 2
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were included in the model regardless of the statistical significance in the bivariate analysis unless a multi-collinearity issue was suspected between variables, because they may represent some important demographic characteristics that may not have been captured by the questionnaire itself. The decision to include other sociodemographic, clinical and psychological characteristics in the model were based on the results of bivariate analyses between each factor and WTP. Statistical significance (p < 0.05) between each factor and WTP in the bivariate analyses were regarded as a suggestion of crude association, and respective factors were included in the model unless there was evidence of the multi-collinearity issue.
Table 1 Demographic characteristics of the study participants. Variables Age (years)
Gender Smoking status Drinking
2.8. Sensitivity analysis
Time to travel to hospital Type of vehicle to the hospital
We performed sensitivity analyses to explore the robustness of the observed findings using different cut-off values of WTP for categorization. The primary cut-off value of WTP was 5 point, and point 4 and 6 on a 0–10 scale was employed for sensitivity analysis.
Self-rated accessibility* Level of education
2.9. Statistical analysis Employment
STATA 14.2 for Windows (STATA Corporation, College Station, TX) was used for statistical analyses. In the descriptive analyses, the mean and standard deviation or median and interquartile range values were used for continuous data depending on the normality of distribution. For categorical data, the frequency and/or proportions of respondents was presented. Group differences (i.e., participants with WTP versus those without WTP) were analysed using an independent t-test or Wilcoxon’s rank-sum test for continuous variables and a Chi-squared test or Fisher’s exact test for categorical variables. Odds ratios and 95 % confidence intervals were used for the presentation of bivariate and multivariate logistic regression analyses. Missing values, if they exist, were not imputed.
Marital status
Type of residence Monthly income (1000 won)
N (%) ≥ 75 65–74 55–64 < 55 Male Female Active Past / none Active (≥once a month) None < 1 hour ≥ 1 hour Public transportation Driving Walking / others Easy to access Not easy to access Elementary school or less Middle or high school College or university Employee Employer Unpaid family worker / others Not working Married (living with spouse) Separated / divorced / never married Alone Family or non-family member I < 1000 K won 1000 K ≤ I < 3000 K won I ≥ 3000 K won
63 (21 %) 100 (33 %) 100 (33 %) 37 (13 %) 169 (56 %) 131 (44 %) 36 (12 %) 264 (88 %) 95 (32 %) 205 (68 %) 203 (68 %) 97 (32 %) 118 (40 %) 173 (57 %) 9 (2 %) 110 (37 %) 190 (63 %) 68 (23 %) 174 (58 %) 58 (19 %) 51 (17 %) 45 (15 %) 11 (3 %) 193 (64 %) 216 (72 %) 84 (28 %) 54 (18 %) 246 (82 %) 141 (47 %) 97 (32 %) 62 (21 %)
frequency (%). * Self-rated accessibility is measured by the questionnaire item “Do you feel comfortable moving from home to the hospital for the clinic?”.
3. Results
the participants were educated at higher than the elementary school level (77 %). Nearly half of the participants had less than a monthly income of 1000,000 won (a value of approximately 886 USD) (Table 1). Most of responders currently had accompanying diseases (82 %), and the major diseases were hypertension (29 %) and diabetes (19 %). The overall health condition and quality of life within the last week were 66.7 (50.0–83.3) (median and IQR) and 63.7 (23.6) (mean and SD), respectively. Almost one-third of participants admitted to anxiety concerning current or future health, and most of the participants responded that they felt comfortable with communicating with the physician (GMS) regarding their own health status (Table 2).
The survey was performed at Pusan National University Yangsan Hospital from February 1, 2017 until June 5, 2017. Among the 458 screened participants, sixty-nine were deemed ineligible. In total, 389 potentially eligible participants were asked to participate in the survey, and 300 agree to participate and responded to the survey (Fig. 1). Metastatic cancer was later identified after completing the survey in one participant. We did not exclude them in the analyses because neither the participants nor clinical or research staff was aware of the metastatic cancer stage at the time of the survey; therefore, information bias due to awareness of metastatic cancer stage was unlikely.
3.2. Experiences and attitudes toward Korean medicine
3.1. Demographic and clinical characteristics
Nearly half of the participants had a lifetime experience of Korean medicine (58 %), mostly for the management of non-cancer conditions (43 %). Most participants did not have prior experience of trial participation, and a small proportion of participants (10 %) responded that they understood the clinical trial of Korean medicine well (Table 3).
The mean age of the participants was 65.6 (SD 10.1) years. There was a slightly higher number of male responders, and non-smokers and non-drinkers accounted for more than half of the respondents. Most of
3.3. Willingness to participate in a hypothetical clinical trial of Korean medicine Ninety-six participants (32 %) responded to have WTP in a hypothetical clinical trial of Korean medicine (Table 3, Appendix 3 and 4). When more information was available on a hypothetical randomised trial comparing Korean medicine combined with usual care to usual care alone, a smaller proportion of participants (27 %) was classified as agreeing with the randomisation process. The most frequent reason for participation and decline of participation was the expectation for an improved health status (46.3 %) and lack of knowledge of Korean
Fig. 1. Flow diagram of the study to willingness to participant in clinical trial of Korean medicine. 3
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3.5. Association between WTP and knowledge and attitude toward trial participation
Table 2 Clinical characteristics of study participants. Variable
N (%)
Cancer Stage
196 (65 %) 102 (34 %) 2 (1 %) 170 (57 %) 130 (43 %) 290 (93 %) 10 (3 %) 147 (49 %) 88 (29 %) 58 (19 %) 20 (7 %) 10 (3.3 %) 8 (2.7 %) 7 (2.3 %) 79 (26 %) 27 (9 %) 66.6 [50.0, 83.3] 63.7 (23.6) 92 (31 %) 279 (93 %)
I/II III IV Lesion Colon Rectum Type of surgery Laparoscopic Open Experience of chemo or radiation therapy Comorbidity Hypertension Diabetes Cardiovascular disease Allergy Liver diseases Musculoskeletal disorder Others Experience of complication after surgery Perception of overall health in the recent week (0–100) * Perception of quality of life in the recent week (0–100) * Anxiety for current/future health Patient-perceived responsiveness of physician
In the bivariate analyses, previous experience of participation in the trials of Korean medicine, reported understanding about the clinical trials of Korean medicine, higher expectation of the improvements in cancer or non-cancer conditions were significantly associated with WTP. The lifetime use of Korean medicine and past experience of participation in clinical trials of other healthcare disciplines showed no significant association with WTP (Appendix 7 and 8). The motivations for trial participation that showed a significant positive association with WTP included altruistic attitude (“To help other patients in future”), being able to contribute to the scientific study, receiving more attention from hospital staff and trust in the physician. Distrust and lack of interest in Korean medicine were significantly negatively associated with WTP (Appendix 9). 3.6. Factors associated with willingness to participate in a clinical trial of Korean medicine Multivariable logistic regression on factors associated with WTP was performed with a priori demographic characteristics (i.e., age, gender, education level, current working or not) and selected factors of participant’s knowledge, perception, and expectation on trials of Korean medicine. Due to the multi-collinearity issue between the working status and level of income, only the working status that showed a significant association in bivariate analysis was included in the final model. WTP in a clinical trial of Korean medicine was independently associated with age between 55–64 (adjusted OR: 3.33; 95 % CI: 1.34–8.26) and age between 65–74 (aOR: 2.66; 95 % CI: 1.07–6.61) but not age less than 55 years (aOR: 1.07; 95 % CI: 0.58–1.97), past experience of participation in trials of Korean medicine (aOR: 5.65; 95 % CI: 1.44–22.14), perceived understanding about clinical trials of Korean medicine (aOR: 3.10; 95 % CI: 1.20–7.96), altruistic reason of trial participation (aOR: 2.40; 95 % CI: 1.33–4.32) and overall expectation of improvement by trial participation (aOR: 2.93; 95 % CI: 1.61–5.35), when adjusted for gender, level of education and working status (Table 4). When participants were asked whether they have willingness to participate in randomised controlled trial of Korean medicine, only altruistic attitude toward trial participation was significantly associated with WTP, independent of other factors in the model (adjusted OR: 2.03; 95 % CI: 1.14–3.61).
mean (SD), median (IQR), frequency (%). Table 3 Participants’ experiences, perceptions and attitudes of Korean medicine. Variable
N (%)
Experience of Korean medicine by KMDs Acupuncture Herbal medicine Cupping Moxibustion Chuna Use of vitamin or dietary supplements Previous experience of clinical trials Korean Medicine Other disciplines Perceived understanding about clinical trials of Korean medicine Agreement with randomization in a clinical trial of Korean medicine Willingness to participation a future trial of Korean medicine
175 (58 %) 166 (55 %) 73 (24 %) 64 (21 %) 56 (19 %) 11 (4 %) 258 (86 %) 16 (5 %) 7 (2 %) 31 (10 %) 82 (27 %) 96 (32 %)
*Each item was rated using a 0 (do not agree at all) to 10 (totally agree) numeric rating scale. Participants who rated the item 6 points or more were counted.
medicine (22.3 %), respectively (Appendix 4).
3.7. Sensitivity analyses The primary analysis which defined participants with WTP as those answered 5–10 points on a 0–10 scale of the WTP question. When participants with WTP was defined as those answered 4 points or more, the prevalence of WTP increased to 47.7 % (n = 143). In this scenario, past experience of participation in and perceived understanding about trials of Korean medicine in the primary multivariable logistic regression was not significantly associated with WTP. When participants with WTP was defined as those answered 6 points or more, the prevalence of WTP decreased to 29.3 % (n = 88). Age-band of 65–74 years lost its significant association with WTP in the multivariable logistic regression analysis. (Appendix 10)
3.4. Association between WTP and sociodemographic and clinical characteristics In the bivariate analyses, the presence of WTP was significantly associated with younger age compared with the oldest age group (i.e., aged 75 years or over), middle to high school level of education compared with elementary school level, and current working. Gender, level of income, marital status, factors concerning travel to the hospital and living alone or cohabiting did not show a significant association with WTP (Appendix 5). Higher level of perceived overall health was significantly associated with WTP, whereas higher level of perceived quality of life was not. Use of vitamin/dietary supplements in the recent year was not significantly associated with WTP. Other clinical characteristics, including stage of cancer, lesion of cancer, past experience of chemotherapy or radiation therapy, anxiety about current or future health status, and perceived responsiveness of the surgeon were found to not be associated with WTP (Appendix 6).
4. Discussion This is the first cross-sectional survey to investigate the WTP of cancer survivors in a clinical trial of Korean medicine in South Korea. In the study, almost one-third (32 %) of colorectal cancer survivors who had participated in the survey at the outpatient clinic in the tertiary care hospital showed WTP in the hypothetical clinical trial of Korean medicine, a number that was significantly higher than that expected (20 4
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Table 4 Factors associated with willingness to participation in a clinical trial of Korean medicine (randomised or not). Factors
Age (year)
Gender Higher level of education (categorized) Currently working Past experience of participation in trials of Korean medicine Perceived understanding about clinical trial Altruism to benefit future cancer patients Expectation of improvement by trial participation
Clinical trial
≥ 75 65–74 55–64 ≤ 54 Male Female Elementary school or below Middle to high school College or university No Yes No Yes No Yes No Yes No Yes
Randomised controlled trial
uOR (95 % CI)
aOR (95 % CI)
p-value
aOR (95 % CI)
p-value
1 2.82 4.00 4.09 1 1.07 1 2.08 2.19 1 1.77 1 7.14 1 5.43 1 3.44 1 4.35
1 2.66 3.33 1.33 1 1.07 1 1.51 1.25 1 1.65 1 5.65 1 3.10 1 2.40 1 2.93
NA 0.035 0.010 0.623 NA 0.839 NA 0.302 0.655 NA 0.119 NA 0.013 NA 0.019 NA 0.004 NA < 0.001
1 1.53 1.85 1.37 1 1.08 1 1.14 2.02 1 1.76 1 0.79 1 1.79 1 2.03 1 1.76
NA 0.331 0.161 0.567 NA 0.795 NA 0.737 0.132 NA 0.065 NA 0.698 NA 0.187 NA 0.015 NA 0.064
(1.24, 6.42) (1.78, 9.00) (1.56, 10.7) (0.66, 1.74) (1.07, 4.05) (0.99, 4.85) (1.07, 2.94) (2.24, 22.8) (2.44, 12.1) (2.06, 5.74) (2.58, 7.37)
(1.07, 6.61) (1.34, 8.26) (0.42, 4.21) (0.58, 1.97) (0.69, 3.29) (0.47, 3.27) (0.88, 3.08) (1.44, 22.1) (1.20, 7.96) (1.33, 4.32) (1.61, 5.35)
(0.65, 3.62) (0.78, 4.38) (0.46, 4.09) (0.59, 1.98) (0.53, 2.43) (0.81, 5.03) (0.97, 3.22) (0.23, 2.65) (0.75, 4.22) (1.14, 3.61) (0.97, 3.19)
Values of unadjusted estimates are from bivariate analysis between each factor and willingness to participate in a clinical trial of Korean medicine. Full list and results of bivariate analyses are available in Appendix 5 and 8. OR: odds ratio; CI: confidence interval.
with 675 respondents among 1000 patients with gastrointestinal and/ or hepatobiliary cancer (as 50.5 % of respondents with colorectal cancer) revealed a mean (SD) WTP of 5.0 (3.1) as measured on a 0–10 visual analogue scale (proportions not reported) [6]. Both studies were conducted to investigate the WTP of the Western medicine oncology clinical trial in tertiary care hospital settings, significantly different from our study contexts. However, whether different study settings, populations and disciplines of interest (i.e., Western or Korean medicine) might be attributable to the observed discrepancy remains unclear and requires further investigation.
%) under the null hypothesis (n = 300; proportion: 0.32; 95 % CI: 0.27 to 0.38; p < 0.001). Participants who were aged between 55–74 years, had past experiences of participation in trials of Korean medicine, had perceived knowledge of clinical trials, had altruistic motivation of participation, and had expectations of beneficial impacts on health by participating in clinical trials, were mostly likely to participate in a future clinical trial of Korean medicine. This likelihood was independent of several sociodemographic and clinical characteristics. When random allocation comparing Korean medicine intervention with control intervention was suggested, fewer participants (27 %) showed WTP in the hypothetical randomised trial of Korean medicine. When factors in the final multivariate logistic regression model were tested using the WTP in the randomised trial of Korean medicine as a dependent variable, altruistic motivation was the only factor that had a significant association with WTP, implying the possible variance of WTP of colorectal cancer survivors depending on the given information and type of group allocation in the future trial of Korean medicine. WTP observed in our study was different from that in previous studies. Among U.S. women with breast cancer who had participated in a cohort study, 49.8 % showed WTP in a trial of acupuncture [5]. One possible explanation for such a difference may be the given information on the suggested trial design when asking for WTP. Nearly half of breast cancer survivors responded to having WTP when provided with the details of the trial intervention (i.e., number of sessions, duration of study) and conditions of interest (i.e., joint pain) were specified [5]. In our study, the type and details of Korean medicine in a future trial were not specified. Although our intention was to investigate WTP for clinical trials of Korean medicine in general (not specifying specific type of intervention, such as acupuncture or herbal medicine), insufficient information regarding the trial design and intervention might have resulted in a lower proportion of participants with WTP in our survey. Other factors, such as gender, ethnicity, type of cancer, and context of survey, may have played a role. However, the source of heterogeneity in the proportion of cancer survivors with WTP and attributable factors for such variance remain unclear and need to be elaborated in future research. Within the Korean context, the estimated proportion of WTP was different from that in previous studies. In a cross-sectional survey involving 524 respondents among 842 patients with various types of cancer in South Korea, 64.7 % showed WTP in a suggested trial when encouraged by their physician [10]. Another cross-sectional survey
4.1. Factors associated with WTP Our findings on factors associated with WTP in a clinical trial of Korean medicine partly resonate with previous studies conducted in a field of Western medicine. In our study, age between 55 to 74 years but not less than 55 years was independently associated with the presence of WTP compared with age over 75 years, implying the possibility of non-linear association between age and WTP. However, insufficient power due to smaller number of participants aged less than 55 years cannot be excluded. Other non-modifiable or difficult-to-modify factors such as proxy of socioeconomic status (i.e., level of education and working status) and for most clinical history was found not to be significantly associated with WTP. A systematic review of barriers to participation in randomised trials found that evidence on the association of illness severity, level of education and age and trial participation remained inconsistent [11]. However, age and gender were significantly associated with participation in U.S. cancer clinical trials [12]. Age, time since the diagnosis of cancer and type of cancer showed a significant association with WTP in diet and exercise intervention trials for 23,841 U.S. cancer survivors [8,13]. In terms of the level of education, our study could not find it as a significant predictor of WTP, while participants with a college education were found to be associated with greater WTP in the study of U.S. women with breast cancer [5]. Re-categorisation in the level of education (i.e., up to high-school versus at least college education) did not affect the significance of its association in our post-hoc sensitivity analysis, indicating the misclassification issue is unlikely to explain the difference (data not shown). A lack of association between the education level and WTP was identified in the Korean survey involving 675 patients with gastrointestinal and hepatobiliary cancer, although the findings were 5
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were patients who had undergone elective laparoscopic or open surgery of colorectal cancer in the hospital. Therefore, most clinical characteristics were extracted from the electronic medical records, reducing risk of inaccuracy and misclassification as well as the risk of recall bias. Trained investigators who were not involved either in surgery or in follow-up management undertook the survey using standardised questionnaire sheets, reducing the potential risk of social desirability bias. There was no missing response on the surveyed items, reflecting the successful data collection process. Several domains of participant characteristics including sociodemographic factors, clinical factors and psychological factors were addressed in the multivariable logistic regression analysis, possibly making the model informative. There are several limitations to be addressed. First, WTP was investigated with very scant information on the trial. Therefore, WTP in the survey may not directly predict the WTP in a real situation with different levels of details of information. Second, the questionnaire was developed based on literature review to investigate potentially important characteristics related to WTP and was refined by the pilot test of a small sample of the patients to enhance readability of the instrument. Nevertheless, formal psychometric validation of the questionnaire was not conducted due to the lack of time and resources. Therefore, we cannot exclude the risk of misclassification and information bias associated with using an unvalidated questionnaire in the survey. Third, we transformed the initial categorical or numerical responses into two or more categories using arbitrary cut-off thresholds to clarify the analyses. This may have introduced a risk of bias due to the misclassification of WTP or factors associated with WTP, as using different cut-off threshold values for categorizing WTP resulted in change of the prevalence of WTP and the magnitude and significance of associated factors. Therefore, estimated prevalence and results of multivariable analysis should be interpreted with caution, and should be regarded as exploratory and hypothesis-generative findings. Fourth, the risk of social desirability bias cannot be entirely excluded and seems somewhat inevitable in the face-to-face survey. Patients who filled out the questionnaire with or without assistance may have responded to the questionnaire differently, although we did not record which participants have received assistance or not. Nevertheless, we have done our best to maintain the neutral attitude and avoid leading questions during the interview. Fifth, the risk of bias due to residual confounding should be considered, possibly arising from unmeasured characteristics such as the level of physical activity, symptoms or discomforts not measured in the diagnosed comorbidity questionnaire item or other psychological traits that may be associated with WTP. Sixth, our findings are from participants who had undergone surgery by the same surgeon (GMS) and had visited the hospital at regular follow-up dates at a local tertiary hospital located in the suburban area of Geong Sang South Province, South Korea. Therefore, the limited generalisability and possibility of unrepresentativeness of our findings should be considered in different contexts and locations. Finally, a substantial number of patients approached by our research team refused to participate in the survey, implying the possibility of selection bias.
unadjusted for possible confounders [6,14]. In a Taiwanese general population, respondents with a college or above level of education showed a significantly less likelihood of WTP than those with a junior high-school or below education when adjusted for gender, marital status and having a biomedicine degree of respondents or family members, indicating heterogeneity in the study population and an increased likelihood of physician distrust in people with a higher level education as contributing factors of the contradictory findings [15]. Collectively, there is no clear explanation for such a variance of association between demographic/clinical characteristics and WTP. Because the association (or lack of association) between demographic/ clinical characteristics and WTP may imply an unequal opportunity of trial participation and reflect under- or over-representation of particular patient subgroups in the trial results [13], the sources of observed heterogeneity (e.g., different study design and contextual factors) need to be explored in further studies Prior experiences and self-reported understandings of the clinical trials of Korean medicine showed a significant association with WTP. The evidence is consistent with our findings, suggesting the importance of knowledge and given information on decision-making regarding trial participation [16,17]. However, the risk of misclassification using a simple single question and absence of detailed information on type of Korean medicine as well as uncertainty due to a small proportion of respondents with WTP should be considered. Igwe (2016) found that modification of knowledge by providing educational information on clinical trial increased participants with WTP [16]. Previous studies have indicated that the information and methods of provision both affect WTP either positively or negatively [11], suggesting knowledge and provided information as potential confounders when investigating WTP. Those who expected to see beneficial effects from Korean medicine as well as those showing altruistic motivation (“to other patients in the future”) were found to have a significant likelihood of reporting WTP. Our findings are in line with the favourable association between expectations of treatment outcomes regarding joint symptoms and WTP in an acupuncture trial in patients with breast cancer [5]. We did not confine the scope of benefits within specific symptoms or problems but asked participants about their general expectations about cancer and non-cancer conditions. Because this is an unvalidated measure of expectation on the benefits of Korean medicine, bias due to misclassification may have resulted in under- or over-estimation of expectation. Randomisation is well-known barrier of trial participation [18–20]. About one in four (27 %) of our participants responded to having WTP in a randomised trial of Korean medicine, although several factors other than random allocation such as the participant’s preference to a particular type of experimental or control intervention, length of follow-up, concerns about adverse events or side effects might also have been attributed to a lower proportion of trial participation. Interestingly, altruistic motivation was the only associated factor of participation in a randomised trial of Korean medicine, independent of other factors that had a significant association with WTP in a clinical trial (not necessarily including a randomised one). Previous studies have consistently reported altruism to benefit other patients as a key facilitator of trial participation [2,20,21]. Based on these findings, we hypothesise that education specifically aimed to highlight altruistic aspects of trial participation may modify a participant’s WTP. This should be explored in further studies focusing on the role of the altruistic attitude of participants in their WTP.
5. Conclusions It is estimated that almost one-third (32 %) of colorectal cancer survivors in South Korea had WTP in a future clinical trial of Korean medicine. Factors associated with WTP included age, favorable psychological attitudes toward Korean medicine and altruistic motivation for trial participation. Limited generalisability, the risk of information bias and residual confounding should be considered when interpreting our findings. Further studies conducted in various types and stages of cancer survivors in a wide range of contexts would be necessary to shed light on the WTP and associated factors in a clinical trial of Korean medicine in cancer survivors.
4.2. Strengths/limitations This is the first cross-sectional study of investigating WTP in a hypothetical clinical trial of Korean medicine in 300 colorectal cancer survivors in South Korea. Formal sample size calculation was conducted with sufficient power to test the null hypothesis. All the participants 6
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Authors’ contributions
References
YHB, GMS, KHK1, MSK, and KHK2 drafted the research design and performed the pilot test of the study questionnaire. KHK1 screened the potentially eligible patients and extracted data on the EMR. YHB and MSK interviewed participants and collected the data. YHB and KHK2 drafted the manuscript. All authors critically reviewed the draft. YHB and KHK2 finalised the masuscript. All authors read and approved the final manuscript. KHK2 supervised the work of YHB and the guarator of the project and the manuscript. KHK1: Kyung Hee Kim. KHK2: Kun Hyung Kim.
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Funding This work was supported by a Grant to Korean Medical Science Research Center for Healthy Aging from the National Research Foundation of Korean Government (2014R1A5A2009936) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1C1B1011136). The funding body has no role in the study design and will not play any role during its execution, analyses, interpretation of the data, or decision to submit the report for publication. Financial disclosure None. Data availability The datasets generated and/or analysed during the current study are not publicly available due to the protection of privacy of participants but are available from the corresponding author on reasonable request. Declaration of Competing Interest None to declare. Acknowledgments We would like to thank cancer survivors who participated in our survey and provided valuable input for this research. This work was supported by a Grant to the Korean Medical Science Research Centre for Healthy Ageing from the National Research Foundation of Korean Government (2014R1A5A2009936) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF2016R1C1B1011136). Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.eujim.2019.101033.
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European Journal of Integrative Medicine journal homepage: www.elsevier.com/locate/eujim
Research paper
Colorectal cancer survivors’ willingness to participate in a hypothetical clinical trial of Korean medicine: A cross-sectional study
T
Yown Hwangboa, Gyung Mo Sonb, Kyung Hee Kimb, Myeong Sook Kwonb, Kun Hyung Kima,c,* a
School of Korean Medicine, Pusan National University, Republic of Korea Department of Surgery, Pusan National University Yangsan Hospital, Republic of Korea c Department of Korean Medicine, Pusan National University Hospital, Republic of Korea b
A R T I C LE I N FO
A B S T R A C T
Keywords: Willingness to participate Korean medicine Clinical trial Colorectal cancer Cross-sectional survey
Introduction: Growing interest in the role of Korean medicine for cancer survivors has prompted the need for clinical trials to guide its rationale use. The study aimed to identify survivors’ willingness to participate (WTP) in a hypothetical clinical trial of Korean medicine and explore associated factors. Methods: Patients were approached to take part in a cross sectional study. Inclusion criteria were; having undergone colorectal cancer surgery (at least 6 months previously) and attending the outpatient clinic of a tertiary hospital. Multivariate logistic regression was performed to investigate factors associated with WTP using a forward selection method. Results: Of 458 patients screened, 300 participated in the survey. Thirty-two percent of participants expressed WTP in a given trial. Multivariate logistic regression analysis (n = 300) demonstrated that WTP was significantly associated with age of 55–64 years (adjusted OR: 3.33; 95 % CI: 1.34–8.26) and 65–74 years (2.66, 1.07–6.61), past experience of participation in a trial of Korean medicine (5.65, 1.44–22.14), perceived understanding about clinical trials (3.10, 1.20–7.96), altruism to benefit future cancer patients (2.40, 1.33–4.32) and expectation for an improved health condition by trial participation (2.93, 1.61–5.35). Conclusions: One-third (32 %) of colorectal cancer survivors showed WTP in a future clinical trial of Korean medicine. Further studies regarding WTP should be conducted in various contexts to inform the design of Korean medicine clinical trials.
1. Introduction Colorectal cancer survivors suffer from various chronic conditions, such as pain, depressive mood, fatigue and other non-specific symptoms [1]. The use of traditional medicine in the cancer care setting is becoming more popular [2–4], although evidence for or against the use of traditional medicine remains inconclusive in most circumstances. Therefore, well-designed comparative studies, especially fully powered high-quality randomised trials, are warranted to address the current evidence-practice gap. The feasibility of conducting trials largely relies on successful participant recruitment and the completion of data acquisition without significant attrition through the entire study process. Identifying willingness to participate (WTP) and associated facilitating factors and barriers is a key process to enhance recruitment and retention feasibility and inform the design of future trials. In previous
literature, the proportion of participants with WTP in various real or hypothetical trials ranged from 11.1% to 88.3 %, and the associated sociodemographic and clinical factors varied between trials, possibly attributable to the difference of the context, population of interest and the research designs [1]. Such large heterogeneity may imply limited generalizability and context-specific characteristics of previous findings and justify further investigation of WTP and associated factors in different settings. WTP and associated factors in randomised trials of acupuncture have been investigated in the USA in women with breast cancer, showing that almost half of the survey respondents expressed WTP but there were variations in barriers among subgroups [5]. In South Korea, WTP of cancer patients in the context of Western medicine trials has been investigated [6]. However, little is known about WTP in clinical trials of Korean medicine for colorectal cancer survivors. Given the
Abbreviations: WTP, willingness to participate; EMR, the electronic medical records; N, number; SD, standard deviation; IQR, inter quartile range; uOR, unadjusted odds ratio; aOR, adjusted odds ratio; O.R., odds ratio; C.I., confidence interval; NA, not applicable ⁎ Corresponding author at: Department of Korean Medicine, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea. E-mail address: [email protected] (K.H. Kim). https://doi.org/10.1016/j.eujim.2019.101033 Received 20 October 2019; Received in revised form 7 December 2019; Accepted 7 December 2019 1876-3820/ © 2019 Elsevier GmbH. All rights reserved.
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different population characteristics and clinical settings, those findings may not be applicable to colorectal cancer survivors who consider participation in a trial of Korean medicine. Considering the growing interest in evidence-based Korean medicine to address the increasing burden of colorectal cancer survivors, the investigation of WTP and associated factors that can inform future well-designed trial is warranted.
clinical trial for a primary question would be adequate given the assumed baseline lay understanding about clinical trials by participants. To identify WTP in a randomised trial, information on the hypothetical parallel randomised trial of Korean medicine with a simple study flowchart was provided (Appendix 11). We did not specify a particular type of Korean medicine intervention in the information because our aim was to clarify the WTP and associated factors for Korean medicine in general. The particular type of control group intervention, such as placebo or active comparators, were also not specified because we hypothesised that participation in a clinical trial may depend on a type of control intervention. Therefore, the general term “control group intervention” was used. The full translated survey questionnaire is available in Appendix 1. Participants were asked to complete the questionnaire with the help of the trained research assistant in a face-to-face manner or independently as preferred. The expected time to complete the survey was 10−20 min, based on the pilot test. Some clinical characteristics that were obtainable in the electronic medical records (EMR) were not completed by the participants and were extracted from the EMR by the trained nurse and research assistant to avoid recall bias and save time for the survey.
1.1. Study objectives This study aimed to investigate WTP in a hypothetical clinical trial of Korean medicine and its associated factors in colorectal cancer survivors. 2. Methods 2.1. Study design and participants This study was a cross-sectional face-to-face survey of colorectal cancer survivors who had previously undergone surgical resection of cancer at the Pusan National University Yangsan Hospital, a tertiary medical centre covering both urban and rural areas in Gyeong Sang South Province. Yangsan city had a population of 320,400 in February 2017 [7]. Three hundred participants were recruited from February 2017 to June 2017. The inclusion criteria were colorectal cancer patients aged 19 years and older who had undergone surgical cancer resection at least six months ago. Those who were younger than 19 years, had cognitive impairment or physical inability, were unable to complete the survey independently or were under assistance were not eligible. Patients with metastatic cancer or those who were on chemotherapy or radiation therapy were also excluded.
2.4. Re-categorisation of continuous and categorical variables Some of the continuous data were categorised based on the arbitrary cut-off values pre-defined by authors. The primary outcome, WTP, was converted into dichotomous variables (having no WTP as a 0–5 score and having WTP as a 6–10 score). We assumed that common threshold (i.e., 6 points or more on a 0–10 scale) of classifying severe cases of symptoms such as pain would be useful for identifying participants who have WTP. Where considered appropriate, other variables were also converted into simpler categorical variables to avoid too few counts and perform meaningful analyses (Appendix 12).
2.2. Recruitment 2.5. Study ethics A registered nurse screened a list of potentially eligible participants in an outpatient department of the study hospital. In the outpatient clinic room, the study surgeon (GMS) asked the patients to respond to the survey. For patients who agreed to participate in the survey, information on the purpose of the survey was explained by the trained research assistants.
This study was approved by the Institutional Review Board of Pusan National University Yangsan Hospital (PNUYH IRB No.: 04-2017-003). The study was carried out in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all participants.
2.3. Survey questionnaire
2.6. Sample size calculation for the cross-sectional study
We developed the study questionnaire based on the review of existing literature investigating factors associated with WTP in various clinical trial settings [1]. A group of investigators including a Korean medical doctor (KHK), a colorectal surgeon (GMS), a surgical nurse and research assistants revised the draft questionnaire. A pilot test was conducted to check the readability and logistics of the questionnaire items in the patients’ perspective and the feasibility of conducting the survey in the outpatient settings. A final version of the survey questionnaire was developed after reflecting the findings from the pilot test. The questionnaire comprised 37 items that covered sociodemographic and clinical characteristics of the participants as well as the participant’s knowledge and perception on participating in a clinical trial of Korean medicine. To identify WTP in clinical trials of Korean medicine, we used the term ‘clinical trial’ as ‘trial that compares the experimental intervention with the control intervention to measure the difference of the clinical outcome, regardless of allocation methods (random allocation, nonrandom allocation or quasi-random allocation)’. Our experience of screening participants in clinical trial of Korean medicine has revealed difficulty of discerning non-randomised and randomised trial by the participants unless further explanation for the allocation scheme was provided. Therefore, we considered that more general description of
Previous literature has shown WTP in a clinical trial is widely distributed from 20 % [8] and 60 % [9], depending on the design, settings and contexts of the investigation. We assumed that the expected proportion of colorectal cancer survivors who may have WTP in the population would be 20 %. The rationale of this assumption is that there have been a few clinical trials of Korean medicine for colorectal cancer patients; thus, relevant information on trials of Korean medicine may not be familiar to them, possibly justifying our assumption on a lower proportion of patients with WTP than those identified in the clinical trial of Western medicine intervention. The α-value for type I error was 0.05. The sample size calculation yielded 246 participants to be investigated to estimate WTP in the population. Considering the possibility of missing answers or logical errors of the answer in 20 % of survey responders, we regarded 300 participants as the required number of subjects in the cross-sectional survey (246 × 1.2 = 295.2 ≒ 300). Formula for sample size calculation is on Appendix 2. 2.7. Development of the multivariable logistic regression model We used a forward selection method to develop the multivariable logistic regression model that explores factors associated with WTP. Age, gender, level of education, employment status and level of income 2
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were included in the model regardless of the statistical significance in the bivariate analysis unless a multi-collinearity issue was suspected between variables, because they may represent some important demographic characteristics that may not have been captured by the questionnaire itself. The decision to include other sociodemographic, clinical and psychological characteristics in the model were based on the results of bivariate analyses between each factor and WTP. Statistical significance (p < 0.05) between each factor and WTP in the bivariate analyses were regarded as a suggestion of crude association, and respective factors were included in the model unless there was evidence of the multi-collinearity issue.
Table 1 Demographic characteristics of the study participants. Variables Age (years)
Gender Smoking status Drinking
2.8. Sensitivity analysis
Time to travel to hospital Type of vehicle to the hospital
We performed sensitivity analyses to explore the robustness of the observed findings using different cut-off values of WTP for categorization. The primary cut-off value of WTP was 5 point, and point 4 and 6 on a 0–10 scale was employed for sensitivity analysis.
Self-rated accessibility* Level of education
2.9. Statistical analysis Employment
STATA 14.2 for Windows (STATA Corporation, College Station, TX) was used for statistical analyses. In the descriptive analyses, the mean and standard deviation or median and interquartile range values were used for continuous data depending on the normality of distribution. For categorical data, the frequency and/or proportions of respondents was presented. Group differences (i.e., participants with WTP versus those without WTP) were analysed using an independent t-test or Wilcoxon’s rank-sum test for continuous variables and a Chi-squared test or Fisher’s exact test for categorical variables. Odds ratios and 95 % confidence intervals were used for the presentation of bivariate and multivariate logistic regression analyses. Missing values, if they exist, were not imputed.
Marital status
Type of residence Monthly income (1000 won)
N (%) ≥ 75 65–74 55–64 < 55 Male Female Active Past / none Active (≥once a month) None < 1 hour ≥ 1 hour Public transportation Driving Walking / others Easy to access Not easy to access Elementary school or less Middle or high school College or university Employee Employer Unpaid family worker / others Not working Married (living with spouse) Separated / divorced / never married Alone Family or non-family member I < 1000 K won 1000 K ≤ I < 3000 K won I ≥ 3000 K won
63 (21 %) 100 (33 %) 100 (33 %) 37 (13 %) 169 (56 %) 131 (44 %) 36 (12 %) 264 (88 %) 95 (32 %) 205 (68 %) 203 (68 %) 97 (32 %) 118 (40 %) 173 (57 %) 9 (2 %) 110 (37 %) 190 (63 %) 68 (23 %) 174 (58 %) 58 (19 %) 51 (17 %) 45 (15 %) 11 (3 %) 193 (64 %) 216 (72 %) 84 (28 %) 54 (18 %) 246 (82 %) 141 (47 %) 97 (32 %) 62 (21 %)
frequency (%). * Self-rated accessibility is measured by the questionnaire item “Do you feel comfortable moving from home to the hospital for the clinic?”.
3. Results
the participants were educated at higher than the elementary school level (77 %). Nearly half of the participants had less than a monthly income of 1000,000 won (a value of approximately 886 USD) (Table 1). Most of responders currently had accompanying diseases (82 %), and the major diseases were hypertension (29 %) and diabetes (19 %). The overall health condition and quality of life within the last week were 66.7 (50.0–83.3) (median and IQR) and 63.7 (23.6) (mean and SD), respectively. Almost one-third of participants admitted to anxiety concerning current or future health, and most of the participants responded that they felt comfortable with communicating with the physician (GMS) regarding their own health status (Table 2).
The survey was performed at Pusan National University Yangsan Hospital from February 1, 2017 until June 5, 2017. Among the 458 screened participants, sixty-nine were deemed ineligible. In total, 389 potentially eligible participants were asked to participate in the survey, and 300 agree to participate and responded to the survey (Fig. 1). Metastatic cancer was later identified after completing the survey in one participant. We did not exclude them in the analyses because neither the participants nor clinical or research staff was aware of the metastatic cancer stage at the time of the survey; therefore, information bias due to awareness of metastatic cancer stage was unlikely.
3.2. Experiences and attitudes toward Korean medicine
3.1. Demographic and clinical characteristics
Nearly half of the participants had a lifetime experience of Korean medicine (58 %), mostly for the management of non-cancer conditions (43 %). Most participants did not have prior experience of trial participation, and a small proportion of participants (10 %) responded that they understood the clinical trial of Korean medicine well (Table 3).
The mean age of the participants was 65.6 (SD 10.1) years. There was a slightly higher number of male responders, and non-smokers and non-drinkers accounted for more than half of the respondents. Most of
3.3. Willingness to participate in a hypothetical clinical trial of Korean medicine Ninety-six participants (32 %) responded to have WTP in a hypothetical clinical trial of Korean medicine (Table 3, Appendix 3 and 4). When more information was available on a hypothetical randomised trial comparing Korean medicine combined with usual care to usual care alone, a smaller proportion of participants (27 %) was classified as agreeing with the randomisation process. The most frequent reason for participation and decline of participation was the expectation for an improved health status (46.3 %) and lack of knowledge of Korean
Fig. 1. Flow diagram of the study to willingness to participant in clinical trial of Korean medicine. 3
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3.5. Association between WTP and knowledge and attitude toward trial participation
Table 2 Clinical characteristics of study participants. Variable
N (%)
Cancer Stage
196 (65 %) 102 (34 %) 2 (1 %) 170 (57 %) 130 (43 %) 290 (93 %) 10 (3 %) 147 (49 %) 88 (29 %) 58 (19 %) 20 (7 %) 10 (3.3 %) 8 (2.7 %) 7 (2.3 %) 79 (26 %) 27 (9 %) 66.6 [50.0, 83.3] 63.7 (23.6) 92 (31 %) 279 (93 %)
I/II III IV Lesion Colon Rectum Type of surgery Laparoscopic Open Experience of chemo or radiation therapy Comorbidity Hypertension Diabetes Cardiovascular disease Allergy Liver diseases Musculoskeletal disorder Others Experience of complication after surgery Perception of overall health in the recent week (0–100) * Perception of quality of life in the recent week (0–100) * Anxiety for current/future health Patient-perceived responsiveness of physician
In the bivariate analyses, previous experience of participation in the trials of Korean medicine, reported understanding about the clinical trials of Korean medicine, higher expectation of the improvements in cancer or non-cancer conditions were significantly associated with WTP. The lifetime use of Korean medicine and past experience of participation in clinical trials of other healthcare disciplines showed no significant association with WTP (Appendix 7 and 8). The motivations for trial participation that showed a significant positive association with WTP included altruistic attitude (“To help other patients in future”), being able to contribute to the scientific study, receiving more attention from hospital staff and trust in the physician. Distrust and lack of interest in Korean medicine were significantly negatively associated with WTP (Appendix 9). 3.6. Factors associated with willingness to participate in a clinical trial of Korean medicine Multivariable logistic regression on factors associated with WTP was performed with a priori demographic characteristics (i.e., age, gender, education level, current working or not) and selected factors of participant’s knowledge, perception, and expectation on trials of Korean medicine. Due to the multi-collinearity issue between the working status and level of income, only the working status that showed a significant association in bivariate analysis was included in the final model. WTP in a clinical trial of Korean medicine was independently associated with age between 55–64 (adjusted OR: 3.33; 95 % CI: 1.34–8.26) and age between 65–74 (aOR: 2.66; 95 % CI: 1.07–6.61) but not age less than 55 years (aOR: 1.07; 95 % CI: 0.58–1.97), past experience of participation in trials of Korean medicine (aOR: 5.65; 95 % CI: 1.44–22.14), perceived understanding about clinical trials of Korean medicine (aOR: 3.10; 95 % CI: 1.20–7.96), altruistic reason of trial participation (aOR: 2.40; 95 % CI: 1.33–4.32) and overall expectation of improvement by trial participation (aOR: 2.93; 95 % CI: 1.61–5.35), when adjusted for gender, level of education and working status (Table 4). When participants were asked whether they have willingness to participate in randomised controlled trial of Korean medicine, only altruistic attitude toward trial participation was significantly associated with WTP, independent of other factors in the model (adjusted OR: 2.03; 95 % CI: 1.14–3.61).
mean (SD), median (IQR), frequency (%). Table 3 Participants’ experiences, perceptions and attitudes of Korean medicine. Variable
N (%)
Experience of Korean medicine by KMDs Acupuncture Herbal medicine Cupping Moxibustion Chuna Use of vitamin or dietary supplements Previous experience of clinical trials Korean Medicine Other disciplines Perceived understanding about clinical trials of Korean medicine Agreement with randomization in a clinical trial of Korean medicine Willingness to participation a future trial of Korean medicine
175 (58 %) 166 (55 %) 73 (24 %) 64 (21 %) 56 (19 %) 11 (4 %) 258 (86 %) 16 (5 %) 7 (2 %) 31 (10 %) 82 (27 %) 96 (32 %)
*Each item was rated using a 0 (do not agree at all) to 10 (totally agree) numeric rating scale. Participants who rated the item 6 points or more were counted.
medicine (22.3 %), respectively (Appendix 4).
3.7. Sensitivity analyses The primary analysis which defined participants with WTP as those answered 5–10 points on a 0–10 scale of the WTP question. When participants with WTP was defined as those answered 4 points or more, the prevalence of WTP increased to 47.7 % (n = 143). In this scenario, past experience of participation in and perceived understanding about trials of Korean medicine in the primary multivariable logistic regression was not significantly associated with WTP. When participants with WTP was defined as those answered 6 points or more, the prevalence of WTP decreased to 29.3 % (n = 88). Age-band of 65–74 years lost its significant association with WTP in the multivariable logistic regression analysis. (Appendix 10)
3.4. Association between WTP and sociodemographic and clinical characteristics In the bivariate analyses, the presence of WTP was significantly associated with younger age compared with the oldest age group (i.e., aged 75 years or over), middle to high school level of education compared with elementary school level, and current working. Gender, level of income, marital status, factors concerning travel to the hospital and living alone or cohabiting did not show a significant association with WTP (Appendix 5). Higher level of perceived overall health was significantly associated with WTP, whereas higher level of perceived quality of life was not. Use of vitamin/dietary supplements in the recent year was not significantly associated with WTP. Other clinical characteristics, including stage of cancer, lesion of cancer, past experience of chemotherapy or radiation therapy, anxiety about current or future health status, and perceived responsiveness of the surgeon were found to not be associated with WTP (Appendix 6).
4. Discussion This is the first cross-sectional survey to investigate the WTP of cancer survivors in a clinical trial of Korean medicine in South Korea. In the study, almost one-third (32 %) of colorectal cancer survivors who had participated in the survey at the outpatient clinic in the tertiary care hospital showed WTP in the hypothetical clinical trial of Korean medicine, a number that was significantly higher than that expected (20 4
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Table 4 Factors associated with willingness to participation in a clinical trial of Korean medicine (randomised or not). Factors
Age (year)
Gender Higher level of education (categorized) Currently working Past experience of participation in trials of Korean medicine Perceived understanding about clinical trial Altruism to benefit future cancer patients Expectation of improvement by trial participation
Clinical trial
≥ 75 65–74 55–64 ≤ 54 Male Female Elementary school or below Middle to high school College or university No Yes No Yes No Yes No Yes No Yes
Randomised controlled trial
uOR (95 % CI)
aOR (95 % CI)
p-value
aOR (95 % CI)
p-value
1 2.82 4.00 4.09 1 1.07 1 2.08 2.19 1 1.77 1 7.14 1 5.43 1 3.44 1 4.35
1 2.66 3.33 1.33 1 1.07 1 1.51 1.25 1 1.65 1 5.65 1 3.10 1 2.40 1 2.93
NA 0.035 0.010 0.623 NA 0.839 NA 0.302 0.655 NA 0.119 NA 0.013 NA 0.019 NA 0.004 NA < 0.001
1 1.53 1.85 1.37 1 1.08 1 1.14 2.02 1 1.76 1 0.79 1 1.79 1 2.03 1 1.76
NA 0.331 0.161 0.567 NA 0.795 NA 0.737 0.132 NA 0.065 NA 0.698 NA 0.187 NA 0.015 NA 0.064
(1.24, 6.42) (1.78, 9.00) (1.56, 10.7) (0.66, 1.74) (1.07, 4.05) (0.99, 4.85) (1.07, 2.94) (2.24, 22.8) (2.44, 12.1) (2.06, 5.74) (2.58, 7.37)
(1.07, 6.61) (1.34, 8.26) (0.42, 4.21) (0.58, 1.97) (0.69, 3.29) (0.47, 3.27) (0.88, 3.08) (1.44, 22.1) (1.20, 7.96) (1.33, 4.32) (1.61, 5.35)
(0.65, 3.62) (0.78, 4.38) (0.46, 4.09) (0.59, 1.98) (0.53, 2.43) (0.81, 5.03) (0.97, 3.22) (0.23, 2.65) (0.75, 4.22) (1.14, 3.61) (0.97, 3.19)
Values of unadjusted estimates are from bivariate analysis between each factor and willingness to participate in a clinical trial of Korean medicine. Full list and results of bivariate analyses are available in Appendix 5 and 8. OR: odds ratio; CI: confidence interval.
with 675 respondents among 1000 patients with gastrointestinal and/ or hepatobiliary cancer (as 50.5 % of respondents with colorectal cancer) revealed a mean (SD) WTP of 5.0 (3.1) as measured on a 0–10 visual analogue scale (proportions not reported) [6]. Both studies were conducted to investigate the WTP of the Western medicine oncology clinical trial in tertiary care hospital settings, significantly different from our study contexts. However, whether different study settings, populations and disciplines of interest (i.e., Western or Korean medicine) might be attributable to the observed discrepancy remains unclear and requires further investigation.
%) under the null hypothesis (n = 300; proportion: 0.32; 95 % CI: 0.27 to 0.38; p < 0.001). Participants who were aged between 55–74 years, had past experiences of participation in trials of Korean medicine, had perceived knowledge of clinical trials, had altruistic motivation of participation, and had expectations of beneficial impacts on health by participating in clinical trials, were mostly likely to participate in a future clinical trial of Korean medicine. This likelihood was independent of several sociodemographic and clinical characteristics. When random allocation comparing Korean medicine intervention with control intervention was suggested, fewer participants (27 %) showed WTP in the hypothetical randomised trial of Korean medicine. When factors in the final multivariate logistic regression model were tested using the WTP in the randomised trial of Korean medicine as a dependent variable, altruistic motivation was the only factor that had a significant association with WTP, implying the possible variance of WTP of colorectal cancer survivors depending on the given information and type of group allocation in the future trial of Korean medicine. WTP observed in our study was different from that in previous studies. Among U.S. women with breast cancer who had participated in a cohort study, 49.8 % showed WTP in a trial of acupuncture [5]. One possible explanation for such a difference may be the given information on the suggested trial design when asking for WTP. Nearly half of breast cancer survivors responded to having WTP when provided with the details of the trial intervention (i.e., number of sessions, duration of study) and conditions of interest (i.e., joint pain) were specified [5]. In our study, the type and details of Korean medicine in a future trial were not specified. Although our intention was to investigate WTP for clinical trials of Korean medicine in general (not specifying specific type of intervention, such as acupuncture or herbal medicine), insufficient information regarding the trial design and intervention might have resulted in a lower proportion of participants with WTP in our survey. Other factors, such as gender, ethnicity, type of cancer, and context of survey, may have played a role. However, the source of heterogeneity in the proportion of cancer survivors with WTP and attributable factors for such variance remain unclear and need to be elaborated in future research. Within the Korean context, the estimated proportion of WTP was different from that in previous studies. In a cross-sectional survey involving 524 respondents among 842 patients with various types of cancer in South Korea, 64.7 % showed WTP in a suggested trial when encouraged by their physician [10]. Another cross-sectional survey
4.1. Factors associated with WTP Our findings on factors associated with WTP in a clinical trial of Korean medicine partly resonate with previous studies conducted in a field of Western medicine. In our study, age between 55 to 74 years but not less than 55 years was independently associated with the presence of WTP compared with age over 75 years, implying the possibility of non-linear association between age and WTP. However, insufficient power due to smaller number of participants aged less than 55 years cannot be excluded. Other non-modifiable or difficult-to-modify factors such as proxy of socioeconomic status (i.e., level of education and working status) and for most clinical history was found not to be significantly associated with WTP. A systematic review of barriers to participation in randomised trials found that evidence on the association of illness severity, level of education and age and trial participation remained inconsistent [11]. However, age and gender were significantly associated with participation in U.S. cancer clinical trials [12]. Age, time since the diagnosis of cancer and type of cancer showed a significant association with WTP in diet and exercise intervention trials for 23,841 U.S. cancer survivors [8,13]. In terms of the level of education, our study could not find it as a significant predictor of WTP, while participants with a college education were found to be associated with greater WTP in the study of U.S. women with breast cancer [5]. Re-categorisation in the level of education (i.e., up to high-school versus at least college education) did not affect the significance of its association in our post-hoc sensitivity analysis, indicating the misclassification issue is unlikely to explain the difference (data not shown). A lack of association between the education level and WTP was identified in the Korean survey involving 675 patients with gastrointestinal and hepatobiliary cancer, although the findings were 5
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were patients who had undergone elective laparoscopic or open surgery of colorectal cancer in the hospital. Therefore, most clinical characteristics were extracted from the electronic medical records, reducing risk of inaccuracy and misclassification as well as the risk of recall bias. Trained investigators who were not involved either in surgery or in follow-up management undertook the survey using standardised questionnaire sheets, reducing the potential risk of social desirability bias. There was no missing response on the surveyed items, reflecting the successful data collection process. Several domains of participant characteristics including sociodemographic factors, clinical factors and psychological factors were addressed in the multivariable logistic regression analysis, possibly making the model informative. There are several limitations to be addressed. First, WTP was investigated with very scant information on the trial. Therefore, WTP in the survey may not directly predict the WTP in a real situation with different levels of details of information. Second, the questionnaire was developed based on literature review to investigate potentially important characteristics related to WTP and was refined by the pilot test of a small sample of the patients to enhance readability of the instrument. Nevertheless, formal psychometric validation of the questionnaire was not conducted due to the lack of time and resources. Therefore, we cannot exclude the risk of misclassification and information bias associated with using an unvalidated questionnaire in the survey. Third, we transformed the initial categorical or numerical responses into two or more categories using arbitrary cut-off thresholds to clarify the analyses. This may have introduced a risk of bias due to the misclassification of WTP or factors associated with WTP, as using different cut-off threshold values for categorizing WTP resulted in change of the prevalence of WTP and the magnitude and significance of associated factors. Therefore, estimated prevalence and results of multivariable analysis should be interpreted with caution, and should be regarded as exploratory and hypothesis-generative findings. Fourth, the risk of social desirability bias cannot be entirely excluded and seems somewhat inevitable in the face-to-face survey. Patients who filled out the questionnaire with or without assistance may have responded to the questionnaire differently, although we did not record which participants have received assistance or not. Nevertheless, we have done our best to maintain the neutral attitude and avoid leading questions during the interview. Fifth, the risk of bias due to residual confounding should be considered, possibly arising from unmeasured characteristics such as the level of physical activity, symptoms or discomforts not measured in the diagnosed comorbidity questionnaire item or other psychological traits that may be associated with WTP. Sixth, our findings are from participants who had undergone surgery by the same surgeon (GMS) and had visited the hospital at regular follow-up dates at a local tertiary hospital located in the suburban area of Geong Sang South Province, South Korea. Therefore, the limited generalisability and possibility of unrepresentativeness of our findings should be considered in different contexts and locations. Finally, a substantial number of patients approached by our research team refused to participate in the survey, implying the possibility of selection bias.
unadjusted for possible confounders [6,14]. In a Taiwanese general population, respondents with a college or above level of education showed a significantly less likelihood of WTP than those with a junior high-school or below education when adjusted for gender, marital status and having a biomedicine degree of respondents or family members, indicating heterogeneity in the study population and an increased likelihood of physician distrust in people with a higher level education as contributing factors of the contradictory findings [15]. Collectively, there is no clear explanation for such a variance of association between demographic/clinical characteristics and WTP. Because the association (or lack of association) between demographic/ clinical characteristics and WTP may imply an unequal opportunity of trial participation and reflect under- or over-representation of particular patient subgroups in the trial results [13], the sources of observed heterogeneity (e.g., different study design and contextual factors) need to be explored in further studies Prior experiences and self-reported understandings of the clinical trials of Korean medicine showed a significant association with WTP. The evidence is consistent with our findings, suggesting the importance of knowledge and given information on decision-making regarding trial participation [16,17]. However, the risk of misclassification using a simple single question and absence of detailed information on type of Korean medicine as well as uncertainty due to a small proportion of respondents with WTP should be considered. Igwe (2016) found that modification of knowledge by providing educational information on clinical trial increased participants with WTP [16]. Previous studies have indicated that the information and methods of provision both affect WTP either positively or negatively [11], suggesting knowledge and provided information as potential confounders when investigating WTP. Those who expected to see beneficial effects from Korean medicine as well as those showing altruistic motivation (“to other patients in the future”) were found to have a significant likelihood of reporting WTP. Our findings are in line with the favourable association between expectations of treatment outcomes regarding joint symptoms and WTP in an acupuncture trial in patients with breast cancer [5]. We did not confine the scope of benefits within specific symptoms or problems but asked participants about their general expectations about cancer and non-cancer conditions. Because this is an unvalidated measure of expectation on the benefits of Korean medicine, bias due to misclassification may have resulted in under- or over-estimation of expectation. Randomisation is well-known barrier of trial participation [18–20]. About one in four (27 %) of our participants responded to having WTP in a randomised trial of Korean medicine, although several factors other than random allocation such as the participant’s preference to a particular type of experimental or control intervention, length of follow-up, concerns about adverse events or side effects might also have been attributed to a lower proportion of trial participation. Interestingly, altruistic motivation was the only associated factor of participation in a randomised trial of Korean medicine, independent of other factors that had a significant association with WTP in a clinical trial (not necessarily including a randomised one). Previous studies have consistently reported altruism to benefit other patients as a key facilitator of trial participation [2,20,21]. Based on these findings, we hypothesise that education specifically aimed to highlight altruistic aspects of trial participation may modify a participant’s WTP. This should be explored in further studies focusing on the role of the altruistic attitude of participants in their WTP.
5. Conclusions It is estimated that almost one-third (32 %) of colorectal cancer survivors in South Korea had WTP in a future clinical trial of Korean medicine. Factors associated with WTP included age, favorable psychological attitudes toward Korean medicine and altruistic motivation for trial participation. Limited generalisability, the risk of information bias and residual confounding should be considered when interpreting our findings. Further studies conducted in various types and stages of cancer survivors in a wide range of contexts would be necessary to shed light on the WTP and associated factors in a clinical trial of Korean medicine in cancer survivors.
4.2. Strengths/limitations This is the first cross-sectional study of investigating WTP in a hypothetical clinical trial of Korean medicine in 300 colorectal cancer survivors in South Korea. Formal sample size calculation was conducted with sufficient power to test the null hypothesis. All the participants 6
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Authors’ contributions
References
YHB, GMS, KHK1, MSK, and KHK2 drafted the research design and performed the pilot test of the study questionnaire. KHK1 screened the potentially eligible patients and extracted data on the EMR. YHB and MSK interviewed participants and collected the data. YHB and KHK2 drafted the manuscript. All authors critically reviewed the draft. YHB and KHK2 finalised the masuscript. All authors read and approved the final manuscript. KHK2 supervised the work of YHB and the guarator of the project and the manuscript. KHK1: Kyung Hee Kim. KHK2: Kun Hyung Kim.
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Funding This work was supported by a Grant to Korean Medical Science Research Center for Healthy Aging from the National Research Foundation of Korean Government (2014R1A5A2009936) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2016R1C1B1011136). The funding body has no role in the study design and will not play any role during its execution, analyses, interpretation of the data, or decision to submit the report for publication. Financial disclosure None. Data availability The datasets generated and/or analysed during the current study are not publicly available due to the protection of privacy of participants but are available from the corresponding author on reasonable request. Declaration of Competing Interest None to declare. Acknowledgments We would like to thank cancer survivors who participated in our survey and provided valuable input for this research. This work was supported by a Grant to the Korean Medical Science Research Centre for Healthy Ageing from the National Research Foundation of Korean Government (2014R1A5A2009936) and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF2016R1C1B1011136). Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.eujim.2019.101033.
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