How to improve participant compliance in clinical trials: A Scoping Review of process factors

The reliability of results can be compromised when subsets of participants who remain on a study differ from those who drop out. Although recent studies have investigated approaches for improving compliance, there has been very little investigation of process factors, regardless of the type of literature and the publication date. factors that may inuence how and why compliance may be successful (or not). Aim To identify process factors that may inuence participant compliance retention in clinical trials, and potential approaches to improve the compliance, from published studies, to facilitate future design and implementation of trials. registries approaches. Results were analysed descriptively, including visualization using word the factors and potential approaches from other researches. But it is possible to miss some articles because the lack of systematic search. Compared with previous studies, the factors and potential approaches provided in our study are more comprehensive. We provide factors and methods for different diseases, populations and interventions. Their conclusions were summarized and analyzed in our study by scoping review. By scoping review, we systematically searched, selected, and integrated existing information to draw a picture of the status and association of compliance studies. In addition, their conclusions were classied and displayed from these studies according to the different stages and characteristics of clinical trials.


studies) .
Process factors that may in uence compliance 70 key factors affecting compliance, grouped into individual, environment, disease, protocol and investigator aspects (Table 1), were nally identi ed. The factors with highest frequencies were: age(54.3%), education(43.4%), economic(41.3%), investigators' skills on communication (40.7%), the adequacy of informed consent(38.5%), gender(38.0%), support from personal social relationship(38.0%), trust for the trials(35.8%), attitude(investigator's attitude towards research and patients)(33.7%) and safety concerns(32.1%). Figure 3 The word cloud about factors affecting the compliance The font size of a word or phrase re ects the frequency of factors in at least two studies.
Potential approaches to improve compliance 44 key themes of potential approaches were eventually included. According the scenarios for actual clinical research, the included potential approaches were divided into three phases: protocol design, recruitment and informed consent, trial implementation period ( Table 2).The potential approaches with highest frequencies were:(1)Researchers should pay attention to the changes on participants' psychological and building good relationships with participant(41.4%); (2)Money, gifts and other compensation can be provided(37.6%); (3)Researchers should carry out the education about compliance during the study (including the knowledge of disease, psychological and medication, trained in the broader context of medical ethics, cultural training)(35.9%); (4)Researchers should give full informed consent to the participant(safety concerns, effect, study protocol, the time they may take,etc)(29.8%);(5) Online reminder (phone, email, etc) should be provided (29.2%).

Discussion
Summary of results 181 publications were included in this review. We reviewed 58 retrospective researches from RCT based on 1,132 clinical trials with 177804 participants, and identi ed 70 factors, which were grouped into individual, disease, environment, protocol and investigators aspects, in uencing participant compliance; and 44 potential approaches, which could be adopted in three phases (protocol design, recruitment and informed consent, the trial implementation period) to improve compliance.

Strengths And Limitations
In past systematic map of digital tools for recruitment and retention we found that process factors were hardly studied [190] , even though these may be important for understanding how and why approaches for improving retention work (or do not work). As far as we know, this is the rst attempt to summarize the factors and the potential approaches of compliance, regardless of the type of literature and the publication date. The results were from 177804 people ( including pregnant women, children, the elderly, college students, addicts, etc), 62 diseases (including cancer, HIV, cancer, diabetes, respiratory diseases, cardiovascular diseases, hypertension, parkinson, alcohol addiction, cocaine dependence, etc ) and 22 countries (high income: the United States, Korea, Canada, Spain, etc; middle income: China, India, etc; lower income: Gambia)(Appendix table 1). The ndings are more universal. Scoping review methods and word cloud were used in our study. We used systematic and extensive approach to identify and analyze literature with the following objectives:1. Examining the scope of the compliance study; 2.Addressing a wide range of the compliance issues; 3.
Including all available research, regardless of study design; 4.Providing a description of the available evidence on compliance issues [189] . But the diverse factors and potential approaches reported in the included studies make it di cult to draw an overall and exact conclusion. In addition, due to the inherent limitations of scoping review and the narrative nature of our topic, our research may focus more on the breadth of information than the depth, so we did not evaluate the quality of the included articles.

Relationship with previous relevant works
The types of previous relevant works included systematic review(5) and traditional literature review (8). Most studies are only conducted on speci c diseases(HIV, stroke, schizophrenia, smoke, Cataract, Amyotrophic lateral sclerosis, Arthritis, Alzheimer). The purpose of systematic review and meta analysis was to test the effect of potential approaches from some trials to improve the compliance. The design of compliance studies includes observational studies, cohort studies, and randomized controlled trials, etc. Variations in research design and lack of overlapping outcome variables often lead to failure to complete systematic reviews. [191] But the in uencing factors of compliance and theoretical perspectives were not provided in depth. The traditional literature review described the factors and potential approaches from other researches. But it is possible to miss some articles because the lack of systematic search. Compared with previous studies, the factors and potential approaches provided in our study are more comprehensive. We provide factors and methods for different diseases, populations and interventions. Their conclusions were summarized and analyzed in our study by scoping review. By scoping review, we systematically searched, selected, and integrated existing information to draw a picture of the status and association of compliance studies. In addition, their conclusions were classi ed and displayed from these studies according to the different stages and characteristics of clinical trials.

Implications for practice and research
The factors identi ed in our study can help researchers predict participants who are less likely to adhere, and develop screening tools to nd e ciently their suitable participants. The better researchers understand these factors, the better it will be to improve participant compliance. The potential approaches for improving compliance we found were generally targeting at the factors we identi ed. However, the factors were not su ciently covered by the potential approaches we found. There is a need to develop more comprehensive potential approaches to address the factors we already know.
In addition, the disagreement between studies demonstrated that these factors may play different roles in different studies, sometimes positive, sometimes negative, and sometimes no effect. For example, age was a commonly reported factor in uencing compliance in the clinical trials, but it was reported that young people may increase or decrease participant compliance. Therefore, most of the identi ed factors have been presented in a neutral form in our study. Researchers should well-thought-out according to their speci c trial context.
The potential approaches mostly mentioned were that researchers should pay attention to the changes on participants' psychological condition, and try their best to build good relationships. Providing compensation (such as gifts, money, postcard) and educating the participants about compliance during the study (including the knowledge of disease, psychology and medication), full implementation of informed consent and reminding participants online (phone, email, etc) were also mentioned by many. Potential approaches still need to be comprehensively developed. Furthermore, adopting potential approaches are often resource demanding. Researchers need to realize this and try to prepare it when planning the trial. Costbene t analysis may be required.
Qualitative methods could be used to make an in-depth exploration to the factors and potential approaches in the future research. More researches are also needed to nd effective potential approaches to encourage the participants to return the sites for follow-up. Implementation research (including, but not limited to, randomized controlled trials) can be used to verify the effectiveness of these included potential approaches by evaluating speci c outcomes, such as compliance rate, compliance improvement rate, retention rate, etc.

Conclusions
We identi ed 70 factors, which were grouped into individual, disease, environment, protocol and investigators aspects, in uencing participant compliance; and 44 potential approaches, which could be adopted in three phases (protocol design, recruitment and informed consent, the trial implementation period) to improve compliance. These factors can help researchers predict participants who are less likely to adhere and develop screening tools to nd e ciently their suitable participants. Before using these potential approaches, researchers should well-thought-out according to budget, the range of disease, population, the design of their research and their usual follow-up procedures.

Declarations
Ethics approval and consent to participate:Not applicable Consent for publication:Not applicable Availability of data and materials:All data and materials can be obtained from the corresponding author.
Competing interests: There are no con icts of interest in this study. [105] CC Xia, YJ Zhu. In uencing factors and pharmaceutical interventions of subjects 'compliance in clinical trials of stroke treatment drugs [J].
[107]SY Liu , ZF Jiang , XY Yu . Nursing intervention of subject compliance in clinical trials of HER-2 positive early breast cancer drugs [J].Chinese Journal of Modern Nursing,2013,19 (27) [108]SZ Hu. Compliance analysis and intervention potential approaches in clinical trials of asthma patients [J]. Health Required (Late Journal), 2013,   Older people may have poorer compliance due to the bad mobility and memory. But they may also be more likely to accept researchers' advice than young people. Young people may also have poorer compliance because they may prefer work or entertainment than participate in clinical trials [21,49,53] .

42/181
Time The more time the patient have, the higher the compliance. [28,30,131] 38/181 Culture The degree of matching between research and culture in uences compliance. [28,82,145]

33/181
Understanding for the trial Patients who understand more about the trial may have higher compliance. However, as their understanding deepens, they may also withdraw because the research does not meet their expectations. [47,61,71] 32/181 Expectations for the trial If the patient's expectations for the study are too high, their compliance may decrease when the treatment effect does not meet expectations. [30,132,184]

31/181
Character The better the character, the higher the compliance [77,79,132]

26/181 Interest in the trial
The more interested in the experiment, the higher the compliance [28,71,131] 25/181 Marriage Married people may have higher compliance [28,30,130]

22/181 Life experience
The greater the impact of clinical trials on the life of the subject, the higher the non-compliance rate [31,61,145] .

18/181
Language The degree of matching between researcher's language and patient's language in uences compliance [49,58,188] .

17/181
Self-e cacy The higher the self-e cacy, the higher the compliance [12,130,145] .

15/181 Previous clinical trial experience
People who have previous clinical trial experience may have higher compliance. [32,67,105,etc] 12/181

Religious
The degree of matching between research and religious in uences compliance. [25,33,92,etc] 10/181 Insurance People who have insurance may have higher compliance [72,95,131,etc] .

5/181
Lost or stolen drugs Lost or stolen drugs may reduce the compliance [59,78,153,etc] .

2/181
Disease Patient's condition* Patient with severe illness have higher compliance than those with less severe illness. But they may also withdraw due to the worsening of their condition [30,46,47,etc] .

39/181 Types of diseases
Different types of diseases also affect patient compliance. For example, patient with cancer have higher compliance in clinical trials compared to chronic diseases [28,157,168,etc] .

22/181
Attitude towards disease People who have positive attitude to disease may have higher compliance [35,97,109,etc] .

16/181
Wanting more information about their illness Patient who want more information about their illness may have higher compliance [30,107,145,etc] .

13/181
Environment Support from surrounding people The more support from surrounding people (family, friends, patient groups), the higher the compliance. [28,31,60,etc] 70/181 Tra c The more convenient the transportation, the higher the compliance [61,124,165,etc]

54/181
Distance Patients who live closer to the study site have higher compliance [28,58,177,etc] 46/181 The environment of treatment The better the treatment environment, the higher the compliance. The compliance of inpatients is higher than outpatients [58,75,154,etc] 28/181

Support from private doctors
The more support from private doctors, the higher the compliance [35,51,53,etc] 23/181 Media Positive guidance from the media may improve compliance [50,63,89,etc] .

49/181
Compensation Patient compliance is higher in studies that have compensation [59,171,etc]

Frequency of treatment
The higher the frequency of the treatment, the worse the compliance [100,149,158,etc] 36/181 The complexity of the study protocol The more complex the study protocol, the higher the compliance [81,146,149,etc]

Duration of treatment
The longer the duration of treatment , the worse the compliance [3,15,43,etc] 28/181 Randomly assigned Patients who are dissatis ed with randomization have worse compliance [132,146,173,etc]

22/181
Different recruitment methods and locations The compliance of patients recruited online is lower than that of patients recruited by private doctors [37,56,101,etc] 15/181 Different study sites Due to factors such as the treatment environment or the investigator, the compliance of patients in different research sites also varies. [158,172,180,etc] 15/181 Feeling to be cured Patients who are consciously cured are more likely to withdraw [52,81,87,etc] 14/181 Intervention Patients who are dissatis ed with intervention (medication, drip, surgery, etc) have worse compliance [15,16,24,etc] 9/181 The way of inspection Patients who are dissatis ed with the way of inspection have worse compliance [55,80,134,etc] 8/181 The level of study High level study can improve patient compliance because of patient trust [71,157,161,etc] 6/181

Researchers' skills on communication
The better the investigator's communication skills, the higher the patient compliance [9,52,82,etc] 75/181 The adequacy of informed consent The more informed consent, the higher the patient compliance [28,81,93,etc] 71/181

Researchers' attitude
The better the researcher's attitude, the higher the patient compliance [10,18,61,etc] 62/181 The relationship between researchers and participants The closer the relationship between the investigator and the patient, the higher the patient compliance [10,18,21,etc] 51/181

Researchers' experience
The richer the researcher's experience, the higher the patient compliance [9,18,105,etc] 38/181 The mastery of the study protocol The better the investigator's mastery of the protocol, the higher the patient compliance [113,130,139,etc] 30/181 The education for participants The more educated (such as standardized selfmanagement, the normative education of taking medicine, etc) the patient, the higher the patient's compliance [30,52,  Reporting the effects at any time during the study to allow patients to dynamically understand their progress 4/181