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      The Impact of an Educational Video on Clinical Trial Enrollment and Knowledge in Ethnic Minorities: A Randomized Control Trial

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          Abstract

          Introduction: Innovative methods to increase awareness about clinical trials and address barriers associated with low participation among racial/ethnic minorities are desperately needed. African Americans comprise 5% of all clinical trial participants, and Hispanics make up 1%. Use of multimedia educational material has shown promise as an effective strategy to increase minority clinical trial enrollment. However, this approach has not been broadly implemented. We tested the effect of a video educational program on clinical trial knowledge and enrollment in a sample of oncology outpatients.

          Methods: A randomized controlled trial was conducted with 63 oncology patients without previous history of clinical trial participation. Participants were randomly assigned to the intervention, to watch a clinical trial educational video in the office, or to the control group which did not receive in-office education. The Clinical Trial Knowledge survey was administered before the intervention and 1 week after the intervention. Participation in clinical trials was assessed 1-year post study participation. Results for white participants and ethnic minorities were compared. Ethnicity was self-reported through the electronic health record and confirmed by self-reporting on questionnaire.

          Results: Sixty-three participants were recruited in this study. At 1-year follow-up, 3 participants enrolled in clinical trials in the study group which had received office-based video intervention and 2 participants enrolled in the control group ( Z = 0.39, p = 0.69). These results were not statistically significant. Impact of the intervention by ethnicity could not be assessed due to low total clinical trial enrollment. The video intervention did not change knowledge, attitudes, or barriers as measured by the Clinical Trial Knowledge Survey. Minority participants did report significantly more negative beliefs and barriers to participation than white participants.

          Conclusions: Increasing awareness and knowledge about clinical trials in underrepresented communities is an important step to providing opportunities for participation. Future studies should focus on how to address the negative expectations of clinical trials and the greater information needs in minority populations. Tailored or personalized messaging may address negative perceptions of clinical trial participation.

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          A systematic review of barriers and facilitators to minority research participation among African Americans, Latinos, Asian Americans, and Pacific Islanders.

          To assess the experienced or perceived barriers and facilitators to health research participation for major US racial/ethnic minority populations, we conducted a systematic review of qualitative and quantitative studies from a search on PubMed and Web of Science from January 2000 to December 2011. With 44 articles included in the review, we found distinct and shared barriers and facilitators. Despite different expressions of mistrust, all groups represented in these studies were willing to participate for altruistic reasons embedded in cultural and community priorities. Greater comparative understanding of barriers and facilitators to racial/ethnic minorities' research participation can improve population-specific recruitment and retention strategies and could better inform future large-scale prospective quantitative and in-depth ethnographic studies.
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            Barriers to recruiting underrepresented populations to cancer clinical trials: a systematic review.

            Racial and ethnic minorities, older adults, rural residents, and individuals of low socioeconomic status are underrepresented among participants in cancer-related trials. The authors conducted a systematic review to determine the barriers to participation of underrepresented populations in cancer-related trials. Their search included English-language publications that reported original data on the recruitment of underrepresented groups to cancer treatment or prevention trials between 1966 and December 2005 in multiple electronic databases. They also hand-searched titles in 34 journals from January 2003 to December 2005 and they examined reference lists for eligible articles. Titles and abstracts were reviewed to identify relevant studies. Data on barriers to participation were synthesized both qualitatively and based on statistically significant associations with trial enrollment. Of 5257 studies that were cited, 65 studies were eligible for inclusion in the current analysis, including 46 studies on recruitment into cancer therapeutic trials, 15 studies on recruitment into prevention trials, and 4 studies on recruitment into both prevention and treatment trials. Numerous factors were reported as barriers to participation in cancer-related trials. However, only 20 of the studies reported statistically significant associations between hypothesized barriers and enrollment. The available evidence had limitations in quality regarding representativeness, justification of study methods, the reliability and validity of data-collection methods, potential for bias, and data analysis. The results indicated that underrepresented populations face numerous barriers to participation in cancer-related trials. The current systematic review highlighting the literature on recruitment of underrepresented populations to cancer trials and may be used as the evidence base toward developing an agenda for etiologic and intervention research to reduce the disparities in participation in cancer-related trials.
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              Strategies for Increasing Recruitment to Randomised Controlled Trials: Systematic Review

              Introduction The randomised controlled trial (RCT) provides the most reliable evidence for evaluating the effects of health care interventions [1],[2], but the successful conduct of clinical RCTs is often hindered by recruitment difficulties [3]. Inadequate recruitment reduces the power of studies to detect significant intervention effects [4], causes delays (which may affect the generalizability of the study if standard care changes over time), increases costs, and can lead to failure to complete trials [5],[6]. With increasing reliance on clinical RCT findings for clinical and regulatory decision making, the success of future RCTs depends on employing effective and efficient methods for recruiting study participants [7]. Historically recruitment of participants for RCTs has been by “trial and error” [8], by using a number of different strategies and modifying strategies according to the observed effects on recruitment. More recently, novel strategies have been developed to facilitate adequate and timely recruitment [3],[4]. Although there have been two previous systematic reviews on strategies to enhance recruitment to research [9],[10], they identified specific individual interventions. However, these interventions could not be combined to offer useful general advice for recruitment for clinical RCTs. The aim of this study was to identify effective recruitment strategies for clinical RCTs by systematically reviewing randomised studies that compare consent rates, or other methods of measuring consent for two or more recruitment methods used, to approach potential RCT participants for trial participation (these studies are termed recruitment trials). Methods A protocol for this systematic review had not been registered before the review commenced, although the abstracts of previous versions of this systematic review were published in 2002 (International Clinical Trials Symposium: improving health care in the new millennium) [11] and 2007 (3rd International Clinical Trials Symposium) [12] (Text S1). Selection Criteria All randomised and quasi-randomised studies that compared two or more methods of recruiting study participants to a real phase III RCT or mock RCT (where no actual trial occurred) were included. Studies that assessed recruitment to observational studies, questionnaires, health promotional activities, and other health care interventions and nonrandomised studies of recruitment strategies were excluded. Where more than one publication of the same study existed, the publication with the most complete data was included. Literature Search Studies were identified from MEDLINE (1950 to April, week 4, 2009), Embase (1980 to week 17, 2009), and The Cochrane Library (Cochrane Library, issue 3, 2009) (Figure 1). The MEDLINE and Embase databases were searched using text words and subject headings (with unlimited truncations) for “recruitment,” “enrolment,” and “accrual” combined with “random” and “trials” and “participate” or “consent” or “recruit” with unlimited truncations. The Cochrane Library was searched using “recruitment” combined with “random and trial,” and “consent or accrual.” The search strategy changed slightly with time as a result of changes in MEDLINE Mesh heading definitions. Reference lists of relevant studies were also searched and non-English language papers were translated. Two of three reviewers (PHYC, AT, or SH) independently screened each study title and abstract for eligibility, retrieved full text articles of all potentially relevant studies, and extracted data from the retrieved papers using a form that was designed by the authors. Disagreements were resolved by discussion with a third reviewer (JCC). 10.1371/journal.pmed.1000368.g001 Figure 1 Literature search. Data Extraction Data were extracted without blinding to authorship, on the recruitment methods evaluated, the population setting, and the trial design, as well as risk of bias items such as randomisation, allocation concealment, blinding of outcome assessors, loss to follow up, and intention-to-treat analysis. These elements were each assessed separately using the method developed by the Cochrane Collaboration [13]. Outcomes Assessed The primary outcome of interest was consent rates for the different recruitment strategies. Because studies differed in definitions of consent rates, where possible we recalculated the consent rate of each recruitment method by dividing the number of participants exposed to the recruitment method who actually consented for clinical study participation by the total number of potential participants exposed to that method (see Figure 2). For studies where information was insufficient to calculate consent rates, other measures of consent success described in the study were reported. For mock trials, willingness to consent to participate (i.e., potential participants acknowledging that they would be willing to participate in the trial or willingness to be contacted for participation in future trials) was the outcome measure. Consent rates and other outcome measures were compared using intention-to-treat analysis. 10.1371/journal.pmed.1000368.g002 Figure 2 Consent rate for RCTs. Statistical Methods Where possible we used relative risk (RR) and their 95% confidence intervals (CIs) to describe the effects of different strategies in individual recruitment trials. Where more than two strategies were used in a single recruitment trial, the numerator and denominator from the standard (control) recruitment strategy was divided by the number of intervention strategies for each comparison so that the control numbers would not be overrepresented [13]. Results Literature Search From 16,703 unique titles and abstracts, 396 articles were retrieved and 37 eligible publications identified (Figure 1). Collectively this total assessed recruitment outcomes in at least 59,354 people who were approached for clinical study participation, of whom 18,812 consented to participate (Table 1). (Not all studies identified the number of potential participants who were approached). 10.1371/journal.pmed.1000368.t001 Table 1 Included studies. Trial Type Author Year of Publication Country of Trial Health Problem Studied Intervention Arms of RCT Recruitment Strategy Studied n Recruited for Trial n Invited to Participate in Trial Treatment Du [39] 2008 USA Lung cancer Mixed treatments (multiple trials) Information provision 26 126 Hutchison [38] 2007 UK Multiple cancers Mixed treatments (multiple trials) Information provision 128 173 Monaghan [51] 2006 Multinational BP control in diabetics Antihypertensive versus placebo Recruiter differences 7,847 167 sites Litchfield [42] a 2005 UK Diabetes Two insulin delivery systems Recruiter differences 73 80 Kimmick [40] 2005 USA Multiple cancers Mixed treatments (multiple trials) Recruiter differences 1,097 unknown Nystuen [31] 2004 Norway Absentee employees Follow up versus standard care Information provision 97 703 Donovan [23] 2003 UK Prostate cancer Surgery versus radiotherapy versus monitoring Recruiter differences 103 150 Coyne [48] 2003 USA Multiple cancers Chemotherapy (multiple trials) Information provision 147 226 Quinaux [41] 2003 France Breast cancer Chemotherapies Recruiter differences 362 unknown Tworoger [37] 2002 USA Breast cancer Aerobic exercises versus stretching Information provision 376 4,999 Fleissig [49] 2001 UK Multiple cancers Mixed treatments (multiple trials) Recruiter differences 205 265 (15 recruiters) Miller [43] 1999 USA Depression Psychotherapy versus antidepressants versus both Recruiter differences 50 347 Cooper [22] 1997 UK Menorrhagia Medical management versus surgery Trial design 187 273 Berner [45] 1997 USA Gynaecological cancers Mixed treatments (multiple trials) Information provision 9 120 Aaronson [20] 1996 The Netherlands Multiple cancers Chemotherapy (multiple trials) Information provision 146 346 Wadland [35] 1990 USA Smoking Nicotine gum versus standard care Information provision 52 104 Simes [33] 1986 Australia Multiple cancers Mixed treatments (multiple trials) Information provision 50 57 Prevention Leira [29] 2009 USA Aspiration pneumonia Ranitidine versus placebo Information provision 52 100 Mandelblatt [3] a 2005 USA Breast cancer Tamoxifen versus Raloxifene Information provision 325 450 Avenell [21] a 2004 UK Fractures Vitamins versus placebo/no treatment Trial design 367 538 Ford [25] 2004 USA Multiple cancers Screening tests versus standard care Information provision 376 12,400 Hemminki [27] a 2004 Estonia Postmenopausal health risks Hormone replacement versus placebo/ no treatment Trial design 1,823 4,295 Larkey [50] 2002 USA cardiovascular disease, cancer and osteoporosis Hormone replacement therapy and dietary modification and calcium and vitamin D supplements Recruiter differences 13 34+ Kendrick [4] 2001 UK Home safety Safety equipment versus usual care Information provision 374 2,397 Kiernan [28] 2000 USA Healthy diet Additional goal setting techniques versus standard care Information provision 9 561 Welton [46] a 1999 UK menopausal symptoms and osteoporosis Hormone replacement therapies versus placebo Trial design 150 492 (438) Rogers [32] 1998 USA Risk for life threatening illness Follow up versus standard care Trial design 44 57 Valanis [34] 1998 USA Lung cancer Vitamins versus placebo Information provision 451 22,546 Mock trial Halpern [47] 2004 USA Hypertension Different hypertensives Incentives+trial design 66–94 142 Ellis [24] 2002 Australia Breast cancer Chemotherapy versus Tamoxifen Information provision 26 180 Martinson [6] a 2000 USA Smoking cessation and prevention Peer, mail, and phone contacts versus standard care Incentives 1,560 4,046 Wragg [44] 2000 UK Postmenopausal health risks Hormone replacement versus placebo Information provision 22 50 Myles [30] 1999 Australia Anaesthesia for surgery Experimental drug versus standard care Trial design 429 770 Weston [5] a 1997 Canada Premature labour Induced labour versus expectant management Information provision 43 90 Gallo [26] a 1995 Italy Hypothetical disease Experimental drug versus standard drug Trial design 1,620 2,035 Llewellyn-Thomas [2] a 1995 Canada Bowel cancer Chemotherapy versus monitoring Information provision 52 102 Simel [36] a 1991 USA Variable presenting health problems Standard versus new medication Trial design 55 100 Total 18,812 59,354+ a Studies showed a statistically significant difference in consent rates between recruitment strategies. BP, blood pressure. Quality of Included Studies There were 23 parallel group RCTs, six quasi-RCTs (including one using paired data), and eight cluster RCTs. Of the 37 included recruitment trials, only 12 studies (32%) had clear allocation concealment, two (4%) specified blinding of outcome assessors (no study had blinding of participants as this would have been difficult to achieve), 15 (40%) recorded loss to follow-up information, and 14 (38%) used intention-to-treat analysis (see Table 2). 10.1371/journal.pmed.1000368.t002 Table 2 Quality of included studies. Trial Type Author Type Of RCT Allocation Concealment Blinding of Outcome Assessors Loss to Follow Up Mentioned Intention-to-Treat Analysis Quality Items Prevention Avenell [21] Parallel Yes No Yes Yes 3 Prevention Rogers [32] Parallel Yes Yes No Yes 3 Treatment Monaghan [51] Cluster RCT Yes Unclear Unclear Yes 2 Treatment Hutchison [38] Parallel Yes Unclear Unclear Yes 2 Treatment Cooper [22] Parallel Yes No No Yes 2 Treatment Tworoger [37] Parallel Unclear Unclear Yes Yes 2 Treatment Coyne [48] Cluster RCT Unclear No Yes Yes 2 Treatment Du [39] Parallel Unclear Yes Yes No 2 Prevention Kendrick [4] Parallel Yes No Yes Unclear 2 Prevention Hemminki [27] Parallel Yes No Unclear Yes 2 Prevention Ford [25] Parallel Unclear No Yes Yes 2 Prevention Leira [29] Parallel No Unclear Yes Yes 2 Mock trial Weston [5] Parallel Yes No Yes Unclear 2 Mock trial Ellis [24] Parallel Yes No Yes Unclear 2 Mock trial Llewellyn-Thomas [2] Parallel Yes No Yes No 2 Mock trial Martinson [6] Cluster RCT Yes No Unclear Yes 2 Treatment Donovan [23] Parallel Yes No No No 1 Treatment Wadland [35] Parallel Unclear No Yes Unclear 1 Treatment Aaronson [20] Parallel Unclear No Yes Unclear 1 Treatment Berner [45] Quasi-RCT No Unclear Yes Unclear 1 Treatment Nystuen [31] Parallel No Unclear Unclear Yes 1 Prevention Larkey [50] Cluster RCT Unclear No Yes No 1 Prevention Valanis [34] Parallel Unclear No No Yes 1 Prevention Welton [46] Quasi-RCT No No Yes Unclear 1 Mock trial Simel [36] Parallel Unclear No No Yes 1 Treatment Quinaux [41] Cluster RCT Unclear Unclear Unclear Unclear 0 Treatment Kimmick [40] Cluster RCT Unclear Unclear Unclear Unclear 0 Treatment Litchfield [42] Cluster RCT Unclear Unclear Unclear Unclear 0 Treatment Fleissig [49] Cluster RCT Unclear No No Unclear 0 Treatment Simes [33] Parallel No No No Unclear 0 Treatment Miller [43] Quasi-RCT No No No Unclear 0 Prevention Kiernan [28] Parallel Unclear No No Unclear 0 Prevention Mandelblatt [3] Quasi-RCT No No Unclear Unclear 0 Mock trial Gallo [26] Parallel Unclear No No Unclear 0 Mock trial Myles [30] Parallel Unclear No No Unclear 0 Mock trial Wragg [44] Quasi-RCT Unclear No No Unclear 0 Mock trial Halpern [47] Paired data No No Unclear Unclear 0 Characteristics of Included Studies Of the 37 included studies, 17 assessed treatment comparisons, 11 were prevention studies, and nine mock studies (where participants declared their willingness to participate in a trial but no actual trial occurred). There were 66 different types of recruitment strategies that were broadly categorised into four groups: novel trial designs (nine studies), recruiter differences (eight studies), incentives (two studies), and provision of trial information (19 studies), with one study looking at both novel trial design and incentives [14]. Standard recruitment is defined as when the investigator invites the potential participant to enrol in the study and treatment allocation is randomly assigned after consent has been given, with routine treatment being provided where consent is not given. Types of Recruitment Strategies Studied Novel trial designs Avenell and Hemminki [15],[16] compared a standard placebo-controlled design with a nonblinded trial design (both for prevention studies) (see Figure 3 and Table 3). In the nonblinded trial design arm, randomisation occurred before participants were approached, and participants were informed of the treatment they were randomised to receive prior to giving consent. Consent rates were higher for the nonblinded trial design compared with standard trial design where randomisation occurred after consent for trial participation (RR 1.14, 95% CI 1.02–1.28 and RR 1.28, 95% CI 1.19–1.37, respectively) [15],[16]. Welton [17] compared a noninferiority clinical study (where both arms of the trial had an active treatment) with a placebo-controlled study of hormone replacement for postmenopausal women. Willingness to enrol in the clinical study appeared to be higher for the noninferiority study compared with the placebo-controlled study, although results were only just statistically significant (39% versus 30%, RR 1.31, 95% CI 1.01–1.70). 10.1371/journal.pmed.1000368.g003 Figure 3 Consent rates for novel trial designs. RR, intervention recruitment strategy/standard recruitment strategy. Used total number/number of intervention strategies to calculate RR, so that the number of patients on standard strategies were not overrepresented; S, random assignment for participants, standard care for nonparticipants; 2, patients are told physician believes the experimental drug may be superior. Increased chance of receiving the experimental drug after consenting; 3, patients are told that they are allowed to increase or decrease their chance of receiving the new experimental drug after consenting; 4, experimental drug for participants, standard care for nonparticipants; 5, standard drug for participants, experimental drug for nonparticipants; 6, random assignment for participants, choice of either treatments for nonparticipants. 10.1371/journal.pmed.1000368.t003 Table 3 Studies of novel trial designs. Study Standard Recruitment Strategy n/N Consent Rate (95% CI) Experimental Recruitment Strategies n/N Consent Rate (95% CI) RR (95% CI) Myles [30] One-sided informed consenta 84/151 56% (48–64) One-sided physician modifiedb 91/150 61% (52–69) 1.10 (0.80–1.50) One-sided patient modifiedc 85/150 57% (48–65) 1.03 (0.75–1.41) Prerandomised to experimental drugd 90/169 53% (45–61) 0.96 (0.70–1.33) Prerandomised to standard druge 79/149 53% (45–61) 0.96 (0.69–1.33) Gallo [26] One-sided informed consenta 521/622 84% (81–87) Prerandomised to experimental drugd 642/730 88% (86–90) 1.05 (0.98–1.12) Prerandomised to standard druge 156/307 51% (45–56) 0.60 (0.53–0.69)f Two-sided informed consentg 301/376 80% (76–84) 0.95 (0.88–1.03) Avenell [21] Standard placebo-controlled design 233/358 65% (60–70) Nonblinded trial design 134/180 74% (67–81) 1.14 (1.02–1.28)f Hemminki [27] Standard placebo-controlled design 796/2,136 37% (35–39) Nonblinded trial design 1,027/2159 48% (46–50) 1.28 (1.19–1.37)f Rogers [32] Opting-in consent for participation 24/32 75% (57–89) Opting-out consent for nonparticipation 20/25 80% (59–93) 1.07 (0.81–1.41) Cooper [22] Standard informed consent 97/138 70% (62–78) Partially randomised patient preferenceh 90/135 67% (58–75) 0.95 (0.81–1.11) Simel [36] Consent for trial of usual treatment versus new treatment that may work twice as fast 35/52 67% (53–80) Consent for trial of usual treatment versus new treatment that may work half as fast 20/48 41% (28–57) 0.62 (0.42–0.91)f Halpern [47] A- US$100 incentive 10% risk of adverse effects 26/64 41% (29–54) 20% risk of adverse effects 23/64 36% (24–49) 1.08 (0.59–2.00) 10% risk of adverse effects 26/64 41% (29–54) 30% risk of adverse effects 18/64 28% (18–41) 1.44 (0.72–2.89) 20% risk of adverse effects 23/64 36% (24–49) 30% risk of adverse effects 18/64 28% (18–41) 1.33 (0.65–2.72) Halpern [47] A- US$1,000 incentive 10% risk of adverse effects 33/64 52% (39–64) 20% risk of adverse effects 26/64 41% (29–54) 1.31 (0.77–2.22) 10% risk of adverse effects 33/64 52% (39–64) 30% risk of adverse effects 23/64 36% (24–49) 1.42 (0.81–2.46) 20% risk of adverse effects 26/64 41% (29–54) 30% risk of adverse effects 23/64 36% (24–49) 1.08 (0.59–2.00) Halpern [47] A- US$2,000 incentive 10% risk of adverse effects 35/64 55% (42–67) 20% risk of adverse effects 29/64 45% (33–58) 1.20 (0.74–1.94) 10% risk of adverse effects 35/64 55% (42–67) 30% risk of adverse effects 25/64 39% (27–52) 1.38 (0.82–2.33) 20% risk of adverse effects 29/64 45% (33–58) 30% risk of adverse effects 25/64 39% (27–52) 1.15 (0.66–2.02) Halpern [47] B- US$100 incentive 10% assigned to placebo 21/62 34% (22–47) 30% assigned to placebo 20/62 32% (21–45) 1.10 (0.55–2.21) 10% assigned to placebo 21/62 34% (22–47) 50% assigned to placebo 19/62 31% (20–44) 1.10 (0.55–2.21) 30% assigned to placebo 20/62 32% (21–45) 50% assigned to placebo 19/62 31% (20–44) 1.00 (0.49–2.06) Halpern [47] B- US$1,000 incentive 10% assigned to placebo 27/62 44% (31–57) 30% assigned to placebo 25/62 40% (28–54) 1.08 (0.61–1.90) 10% assigned to placebo 27/62 44% (31–57) 50% assigned to placebo 23/62 37% (25–50) 1.17 (0.65–2.10) 30% assigned to placebo 25/62 40% (28–54) 50% assigned to placebo 23/62 37% (25–50) 1.08 (0.59–1.99) Halpern [47] B- US$2,000 incentive 10% assigned to placebo 28/62 45% (33–58) 30% assigned to placebo 26/62 42% (30–55) 1.08 (0.61–1.90) 10% assigned to placebo 28/62 45% (33–58) 50% assigned to placebo 27/62 44% (31–57) 1.00 (0.58–1.73) 30% assigned to placebo 26/62 42% (30–55) 50% assigned to placebo 27/62 44% (31–57) 0.93 (0.53–1.64) Welton [46] Standard placebo-controlled design 65/218 30% (24–36) Noninferiority trial design 85/218 39% (33–46) 1.31 (1.01–1.70)f RR, experimental recruitment strategy/standard recruitment strategy. Used total number/number of experimental strategies to calculate RR, so that standard was not overrepresented. Halpern's study used each participant more than once. a Random assignment for participants, standard care for nonparticipants. b Patients told physician believes the experimental drug may be superior. Increased chance of receiving the experimental drug after consenting. c Patients are told that they are allowed to increase or decrease their chance of receiving the new experimental drug after consenting. d Experimental drug for participants, standard care for nonparticipants. e Standard drug for participants, experimental drug for nonparticipants. f Studies showed a statistically significant difference in consent rates between recruitment strategies. g Random assignment for participants, choice of either treatments for nonparticipants. h Patients could choose to be randomised or choose their own treatment, but only those who chose to be randomised were compared with standard treatment. Gallo and Myles (both for mock studies) compared standard randomisation (random assignment for all participants and standard care for nonparticipants) with different types of randomisation designs [18],[19]. Strategies included increasing or decreasing the chance of receiving the experimental treatment; experimental treatment for all participants and standard treatment for nonparticipants (where potential participants are informed that they have been randomised to receive the experimental treatment, but if they do not consent, they would receive the standard treatment); standard care for all participants and experimental treatment for nonparticipants (where potential participants are informed that they have been randomised to receive the standard treatment, but if they do not consent, they would receive the experimental treatment); and random assignment of treatment for participants and choice of treatment for nonparticipants. The only randomisation strategy that influenced consent was the “prerandomisation to standard drug” (standard care for all participants and experimental treatment for nonparticipants) in Gallo's study [18], which significantly reduced the consent rate compared with standard randomisation (RR 0.60, 95% CI 0.53–0.69) [18]. However, this was not demonstrated in Myles' study [19]. Cooper compared standard consent with partially randomised patient preference where patients could choose to be randomised or choose their own (medical or surgical) treatment [20]. Patients who chose their own treatment were excluded in our analysis, as choice of treatment conflicts with the purposes of random allocation of treatment, and only patients who chose to be randomised were compared with those receiving standard RCT consent (where they were offered the opportunity to participate in a clinical study where treatment was randomly allocated for participants). This study tested whether allowing a patient choice of treatments increased consent for choosing to have their treatment randomised, compared with simply inviting them to participate in a clinical RCT (without mentioning choice of treatment). There was no difference in consent rates between the standard consent and choosing to be randomised (RR 0.95, 95% CI 0.81–1.11). Rogers compared “opting in” with “opting out” [21] where consent was sought for participation or for nonparticipation, respectively. In the “opting out” arm, consent rate for clinical study participation was calculated as the proportion who did not sign the consent form (for refusing participation). There was no difference in consent rates between the two groups (RR 1.07, 95% CI 0.81–1.41). Simel compared consenting to a clinical study assessing standard medication versus a new medication that worked twice as fast with a clinical study comparing standard medication with a new medication that worked half as fast as the standard medication [22]. Participants were not informed that this was a mock trial. This study was designed to assess patients' competence and judgement regarding clinical study participation. Not surprisingly, more patients consented to a clinical study comparing the faster new medication than to a clinical study comparing a slower new medication (67% versus 41%, RR 0.62, 95% CI 0.42–0.91), with a more marked difference among those who voluntarily mentioned the medication's speed of action as a factor in their decision regarding clinical study participation, which may reflect better understanding of the trial information. Halpern [14] used a factorial design to assess willingness to participate in a number of mock trials using paired data from the same individuals with variations in clinical study designs (as well as variation in monetary incentives, which will be discussed later under “incentives”). There were no differences in consent rates statistically. Recruiter differences Eight recruitment trials compared recruiter differences (see Figure 4 and Table 4). Three cluster RCTs compared different strategies for engaging recruiters (e.g., standard contact versus additional monitoring and contact with recruiters [23]–[25]). Outcome measures were different for each of the studies and therefore results could not be combined. In Quinaux's study, 186 patients from 34 control centres enrolled compared with 176 total patients from 34 monitored centres [23]. In Kimmick's study, 1,161 elderly patients (36% of total patients in first year and 31% in second year) from the control centres enrolled compared with 1,075 (32% in first year and 31% in second year) from the centres who received additional training and contact with investigators [24]. Monaghan's study assessed median number of patients recruited per site with 37.0 patients from the 82 control sites compared with 37.5 patients from the 85 sites with increased contacts with investigators [25]. In all three studies, increased contact with investigators did not statistically increase consent rates, and appeared to actually lower enrolment. One recruitment trial that compared untrained recruiters with training of recruiters [26] found statistically more patients enrolled when the recruiter was trained (28 trained recruiters enrolled 13 patients versus 28 untrained recruiters who enrolled no patients). Fleissig compared standard recruitment with providing recruiters with information about patient preferences [27], with no differences in consent rates between the two methods (RR 1.09, 95% CI 0.96–1.25). 10.1371/journal.pmed.1000368.g004 Figure 4 Consent rates for recruiter differences. RR, intervention recruitment strategy/standard recruitment strategy. 10.1371/journal.pmed.1000368.t004 Table 4 Studies of recruiter differences. Study Standard Recruitment Strategy n/N Consent Rate (95% CI) Experimental Recruitment Strategies n/N Consent Rate (95% CI) RR (95% CI) Donovan [23] Recruitment by urologist 53/75 71% (59–81) Recruitment by nurse 50/75 67% (55–77) 0.94 (0.76–1.17) Miller [43] Recruitment by senior investigator 28/162 17% (12–24) Recruitment by research assistant 22/185 12% (8–17) 0.69 (0.41–1.15) Fleissig [49] Standard consent, doctors not aware of patients' personal preferences 96/130 74% (65–81) Doctors shown patient's responses to questionnaire regarding personal preferences and trial participation before recruiting patients for trial 109/135 81% (73–87) 1.09 (0.96–1.25) Litchfield [42] Paper-based data recording 28/28 screened 100% (88–100) Internet data capture 45/52 screened 87% (74–94) 0.87 (0.78–0.96)a Quinaux [41] Centres not monitored 186/34 centres Monitored centres 176/34 centres Larkey [50] Recruiters not trained 0/28 recruiters Recruiters trained 13/28 recruiters Kimmick [40] Standard recruitment, website access and periodic notification 777 (year 1)+384 (year 2) = 1,161 Additional seminar, educational materials, list of available protocols, email and mail reminders, and case discussion seminars for recruiters 691 year 1)+384 (year 2) = 1,075 Monaghan [51] Usual communication 37 (median) per site at 82 sites Frequent email contact and individual feedback about recruitment to the recruiter 37.5 (median) per site at 85 sites RR, experimental recruitment strategy/standard recruitment strategy. a Studies showed a statistically significant difference in consent rates between recruitment strategies. Donovan and Miller compared recruiter roles (doctor versus nurse RR 0.94, 95% CI 0.76–1.17 [28], and senior investigator versus research assistant RR 0.69, 95% CI 0.41–1.15 [29]). Although there was no difference in consent rates between the recruiters, costs were higher for the more senior person (mean cost of £43.29 versus £36.40 and US$78.48 versus US$50.28 per patient randomised, respectively). Litchfield compared internet-derived database handling with paper-based database handling [30]. Although proportionately more patients enrolled with the paper-based database, the internet database was more efficient (with shorter time required for data collection and more patients being exposed to the trial). 100% of paper-based database versus 87% internet database groups enrolled (RR 0.87, 95% CI 0.78–0.96), with the internet database being preferable for recruiters. Incentives Martinson and Halpern assessed incentives for increasing recruitment (see Figure 5 and Table 5) [14],[31]. In the Martinson study, compared to no incentives, any monetary incentive increased survey response rates and willingness to be contacted regarding a smoking cessation trial. The study did not measure actual recruitment to the clinical study. Consent rate for no incentives was 29% compared with 41% for prepaid US$2 cash incentive (RR 1.43, 95% CI 1.19–1.72); 44% for US$15 cash incentive contingent on completion of survey (RR 1.53, 95% CI 1.28–1.84); and 39% for US$200 prize draw (RR 1.36, 95% CI 1.13–1.64). 10.1371/journal.pmed.1000368.g005 Figure 5 Consent rates for incentives. RR, intervention recruitment strategy/standard recruitment strategy. Used total number/number of intervention strategies to calculate RR, so that the number of patients on standard strategies were not overrepresented; S, random assignment for participants, standard care for nonparticipants; 1, small incentives (US$2 prepaid cash incentive); 2, larger incentive (US$15) contingent on response; 3, US$200 prize draw. 10.1371/journal.pmed.1000368.t005 Table 5 Studies of incentives. Study Standard Recruitment Strategy n/N Consent Rate (95% CI) Experimental Recruitment Strategies n/N Consent Rate (95% CI) RR (95% CI) Martinson [6] No incentives 288/996 29% (26–32) US$2 small prepaid cash 423/1,021 41% (38–45) 1.43 (1.19–1.72)a Large cash incentives contingent on response (US$15) 452/1,021 44% (41–47) 1.53 (1.28–1.84)a US$200 prize draw 397/1008 39% (36–42) 1.36 (1.13–1.64)a Halpern [47] A-10% risk of adverse effect US$100 26/64 41% (29–54) US$1,000 33/64 52% (39–64) 0.76 (0.45–1.30) US$100 26/64 41% (29–54) US$2,000 35/64 55% (42–67) 0.72 (0.43–1.21) US$1,000 33/64 52% (39–64) US$2,000 35/64 55% (42–67) 0.94 (0.60–1.48) Halpern [47] A-20% risk of adverse effect US$100 23/64 36% (24–49) US$1,000 26/64 41% (29–54) 0.92 (0.30–1.70) US$100 23/64 36% (24–49) US$2,000 29/64 45% (33–58) 0.80 (0.45–1.43) US$1,000 26/64 41% (29–54) US$2,000 29/64 45% (33–58) 0.87 (0.50–1.51) Halpern [47] A-30% risk of adverse effect US$100 18/64 28% (18–41) US$1,000 23/64 36% (24–49) 0.75 (0.37–1.53) US$100 18/64 28% (18–41) US$2,000 25/64 39% (27–52) 0.69 (0.35–1.39) US$1,000 23/64 36% (24–49) US$2,000 25/64 39% (27–52) 0.92 (0.50–1.70) Halpern [47] B- 10% assigned to placebo US$100 21/62 34% (22–47) US$1,000 27/62 44% (31–57) 0.79 (0.43–1.45) US$100 21/62 34% (22–47) US$2,000 28/62 45% (33–58) 0.70 (0.43–1.45) US$1,000 27/62 44% (31–57) US$2,000 28/62 45% (33–58) 1.00 (0.58–1.73) Halpern [47] B- 30% assigned to placebo US$100 20/62 32% (21–45) US$1,000 25/62 40% (28–54) 0.77 (0.40–1.48) US$100 20/62 32% (21–45) US$2,000 26/62 42% (30–55) 0.77 (0.40–1.48) US$1,000 25/62 40% (28–54) US$2,000 26/62 42% (30–55) 1.00 (0.56–1.80) Halpern [47] B- 50% assigned to placebo US$100 19/62 31% (20–44) US$1,000 23/62 37% (25–50) 0.83 (0.42–1.64) US$100 19/62 31% (20–44) US$2,000 27/62 44% (31–57) 0.71 (0.38–1.36) US$1,000 23/62 37% (25–50) US$2,000 27/62 44% (31–57) 0.86 (0.48–1.54) RR, experimental recruitment strategy/standard recruitment strategy. Used total number/number of experimental strategies to calculate RR, so that standard was not overrepresented. Halpern's study used each participant more than once. a Studies showed a statistically significant difference in consent rates between recruitment strategies. The Halpern study assessed the effect of variations in monetary incentives on the willingness to participate in a number of mock clinical studies (of varying trial designs that was mentioned earlier). Patients' willingness to participate increased as the payment level increased from US$100 to US$2,000 irrespective of the risk of adverse effect and risk of being assigned to placebo, although the difference was not statistically significant. Methods of providing information Nineteen recruitment trials compared different methods of providing information to participants, including how the information was presented and what information was provided (see Figure 6 and Table 6). 10.1371/journal.pmed.1000368.g006 Figure 6 Consent rates for methods of providing information. RR, intervention recruitment strategy/standard recruitment strategy. Used total number/number of intervention strategies to calculate RR, so that the number of patients on standard strategies were not overrepresented; S, standard informed consent; B, bulk mailing; 1, enhanced recruitment letter and screening by African American interviewer; 2, enhanced recruitment letter, screening by African American interviewer and baseline information collected via telephone interview; 3, enhanced recruitment letter, screening by African American interviewer and church-based project sessions; 4, bulk mailing with letter; 5, first-class mailing; 6, first-class mailing with letter. 10.1371/journal.pmed.1000368.t006 Table 6 Studies of methods of providing information. Study Standard Recruitment Strategy n/N Consent Rate (95% CI) Experimental Recruitment Strategies n/N Consent Rate (95% CI) RR (95% CI) Kendrick [4] Standard informed consent (mailing) 157/1,194 13% (11–15) Additional home safety questionnaire 217/1,203 18% (16–20) 1.37 (1.14–1.66)a Kiernan [28] Standard informed consent (mailing of flyer) 0/191 0% (0–2) Additional personal letter (combination of general letter+Hispanic specific letter) 9/370 2% (1–5) 9.83 (0.58–168.04) Valanis [34] Standard informed consent (mailing) 225/11,273 2% (2–6) Advanced postcard 1 wk prior to mailing of recruitment packet 226/11,273 2% (2–2) 1.0 (0.84–1.21) Nystuen [31] Standard informed consent (mailing) 42/347 12% (9–16) Additional reminder phone call for nonresponders 55/356 15% (12–19) 1.28 (0.88–1.85) Ford [25] Standard informed consent (mailing)+screeningb 95/3,297 3% (2–4) Enhanced recruitment letter+screening by African American interviewer 78/3,079 3% (2–3) 0.87 (0.58–1.31) Enhanced recruitment letter+screening by African American interviewer+baseline information collected via telephone interview 87/3,075 3% (2–3) 0.97 (0.65–1.45) Enhanced recruitment letter+screening by African American interviewer+church-based project sessions 116/2,949 4% (3–5) 1.35 (0.92–1.99) Tworoger [37] Bulk mailing no letters 86/1,250 7% (6–8) Bulk mailing with letter 87/1,251 7% (6–9) 1.00 (0.67–1.50) First class mailing no letters 102/1,249 8% (7–10) 1.17 (0.79–1.75) First class mailing with letters 101/1,249 8% (7–10) 1.16 (0.78–1.73) Leira [29] Standard informed consent 25/50 50% (36–65) Advanced notification with phone and fax 27/50 54% (39–68) 1.08 (0.74–1.57) Llewellyn-Thomas [2] Tape recording of trial information 21/50 42% (28–57) Interactive computer program for participants 31/50 62% (47–75) 1.48 (1.00–2.18)a Weston [5] Standard informed consent 17/48 35% (22–51) Additional video about the health condition 26/42 62% (46–76) 1.75 (1.11–2.74)a Berner [45] Standard informed consent (verbal) 4/50 7% (2–19) Additional written cancer-specific information 4/56 7% (2–17) 0.89 (0.24–3.38) Ellis [24] Standard informed consent 14/42 33% (20–50) Additional education booklet on trials 12/41 29% (16–46) 0.88 (0.46–1.66) Du [39] Standard informed consent 10/63 16% (8–27) Additional video about clinical trials 16/63 25% (15–38) 1.60 (0.79–3.25) Hutchison [38] Standard informed consent 66/87 76% (66–84) AVPI tool to explain about trials, video+DVD/CD 62/86 72% (61–81) 0.95 (0.80–1.13) Coyne [48] Standard informed consent 93/137 68% (59–76) Easy-to-read consent statement 67/89 75% (65–84) 1.11(0.94–1.31) Wadland [35] Patients reading trial information 25/53 47% (33–61) Study coordinator reading and explaining the study to patients 27/51 53% (39–67) 1.12 (0.76–1.65) Aaronson [20] Standard informed consent 78/90 87% (78–93) Additional phone-based contact with oncology nurse 68/90 76% (65–84) 0.87 (0.76–1.01) Mandelblatt [3] Standard informed consent (brochure) 147/218 67% (61–74) Additional brief educational session and discussion about the trial 178/232 77% (71–82) 1.14 (1.01–1.28)a Simes [33] Total disclosure 23/28 82% (63–94) Individual approach 27/29 93% (77–99) 1.13 (0.93–1.38) Wragg [44] Explicit informationc 8/26 31% (14–52) Ambiguous informationd 14/24 58% (37–78) 1.90 (0.97–3.70) RR, experimental recruitment strategy/standard recruitment strategy. Used total number/number of experimental strategies to calculate RR, so that standard was not overrepresented. a Studies showed a statistically significant difference in consent rates between recruitment strategies. b Standard informed consent and screening (used total number/number of experimental strategies to calculate RR, so that standard was not overrepresented). c Provides the current best estimates of effect of the experimental treatment. d Emphasises the current state of uncertainty. There were six recruitment trials that related to mailing of recruitment material for the clinical study. The methods used to enhance recruitment were the addition of: a questionnaire that focused on the health problem studied (Kendrick [32]); a personal letter inviting participation (Kiernan and Tworoger [33],[34]); use of bulk mailing or first class stamps (Tworoger [34]); an advanced postcard alerting recipients to look for the recruitment packet (Valanis [35]); a reminder phone call for nonresponders of mailed recruitment material (Nystuen [36]); and increasingly intensive interventions (for African Americans), which included a follow-up eligibility-screening phone call, an enhanced recruitment letter featuring a prominent African American man, recruitment by an African American member of the research team, and involvement of church-based project sessions (Ford [37]). Kendrick's addition of the questionnaire that focused on the health problem studied (RR 1.37, 95% CI 1.14–1.66) [32] was the only mailing strategy that increased the consent rate compared with standard mailing of recruitment material. The personal letter [33],[34] using bulk mail or first class mail [34], advanced postcard warning [35], and reminder phone calls [36] did not significantly increase consent rates (see Table 6). Leira compared standard consent (being invited to participate in the clinical study when the investigators met the patient during helicopter retrievals) with advanced notification of the clinical study with telephone and faxing of informed consent documents prior to arrival of investigators in the helicopter [38]. The intention-to-treat analysis showed no statistical difference between the two recruitment strategies (RR 1.08, 95% CI 0.74–1.57), although 42% of the intervention group did not actually receive the intervention (fax and telephone call) because of technical and logistic reasons. Coyne compared an easy-to-read consent statement with standard consent [39] but showed no significant difference in consent rates (RR 1.11, 95% CI 0.94–1.31). Three recruitment trials looked at increasing participants' understanding of the clinical trial process, which did not appear to affect recruitment [40]–[42]. Ellis compared standard informed consent with the addition of an educational booklet on clinical trials [40]. There was no difference in consent rates (unadjusted) between the two groups (RR 0.88, 95% CI 0.46–1.66). However, after adjusting for potential confounders (demographic variables, disease variables, preference for involvement in clinical decision making, anxiety, depression, and attitudes to clinical trials), participants receiving the educational booklets were significantly less likely to consent to clinical study participation (OR 0.22, 95% CI 0.04–1.0). Du compared standard care with the addition of a brief video about cancer clinical studies among patients with lung cancer [41]. Consent rates were not statistically different between the two groups. Hutchison compared standard care (where patients discuss clinical care and clinical study participation with the administration of a trial-specific information sheet and consent form) with the addition of an audiovisual patient information tool (with choice of video, CD-Rom, or DVD format), which addressed clinical trial information [42], with no difference in consent rates between the two groups (76% versus 72%, RR 0.95, 95% CI 0.80–1.13). Three recruitment trials assessed strategies that aim to increase participants' understanding of their underlying condition. Llewellyn-Thomas compared tape recorded reading of clinical study information with an interactive computer program where participants (who were oncology patients receiving radiation therapy) were actively involved in the information search process [43]. The consent rate was higher for participants in the interactive group (RR 1.48, 95% CI 1.00–2.18). Weston compared standard informed consent with the addition of a video explaining trial information and the health problem studied [44]. The consent rate was higher in the video group when initially assessed (RR 1.75, 95% CI 1.11–2.74), but this did not reach statistical significance at 2 wk follow-up (not shown on Table 6). Berner's recruitment trial compared standard care (verbal communication) with the addition of patient information files containing clinical information on cancer specific to the patient [45]. There was no difference in the rate of recruitment to cancer trials in both groups (7% versus 7%, RR 0.89, 95% CI 0.24–3.38), although not all patients were eligible for clinical study enrolment. Three recruitment trials compared standard consent with additional personal contact with research staff (a study coordinator reading and explaining the clinical study, Wadland [46]; additional phone-based contact with an oncology nurse, Aaronson [47]; and an additional educational session about the disease and risks and benefits of clinical study participation for an oncology prevention study, Mandelblatt [48]). There was no difference in consent rates between standard consent and the study coordinator reading and explaining the clinical study (RR 1.12, 95% CI 0.76–1.65) [46] or additional phone-based contact with the oncology nurse (RR 0.87, 95% CI 0.76–1.01) [47]. However there was higher consent for participants who attended the education session (RR 1.14, 95% CI 1.01–1.28) [48]. There were two recruitment trials assessing framing of recruitment information. In Simes' 1986 trial of recruitment for a cancer treatment study [49], total disclosure of information about the clinical study was compared with an individual approach where doctors informed patients about the clinical study in a manner they thought best. This study assessed both willingness to enrol in the clinical study and actual study participation. There were no differences in actual consent rates between the total disclosure and individual approach groups (RR 1.13, 95% CI 0.93–1.38). However, actual consent rates were higher than the stated willingness to participate in the clinical study (actual consent rates were 82% and 93% in the total disclosure and individual approach groups, respectively, compared with rates of 65% and 88%, respectively, for willingness to participate in the clinical study). Wragg compared framing of recruitment information explicitly (to provide the best current estimates of effect for the experimental treatment) with framing information ambiguously (to emphasise the uncertainty and relative costs and benefits of the experimental treatment) [50]. There was no difference in consent rates between the “ambiguously framed” group and the “explicitly framed” group (RR 1.90, 95% CI 0.97–3.70). Discussion Trials of recruitment strategies have evaluated all steps in the recruitment process, including different methods of trial design, randomisation, provision of information, and recruiter differences. In this systematic review, we found that strategies that increased potential participants' awareness of the health problem being studied by engaging them in the learning process significantly increased consent rates (both for “real” and mock trials). These strategies included the addition of a questionnaire that focused on the health problem studied and additional educational sessions, videos, and interactive programs about the diseases studied [32],[43],[44],[48]. Strategies that increased understanding of the clinical trial process (e.g., provision of an educational booklet [40], video [41], or audiovisual patient information tool [42] on clinical trials or provision of an easy-to-read consent statement [39]) showed no evidence of improved recruitment. This finding suggests that it is increased education about the health problem being studied rather than education about the clinical trial process that increased trial participation. There were insufficient data to evaluate whether the effects of the different recruitment strategies were constant across all health conditions, but no there was no clear trend for these strategies to be context specific (see Table 1). The recruitment trials on how recruitment information was provided (the technique of information presentation, how information was framed, who presented the information, and when the information was presented) did not show a difference between strategies, demonstrating that how or when the information was presented or who presented the information did not influence recruitment, but rather the information provided. A recent study (which was published after completion of our last search update) also showed that publicity about the trial did not increase recruitment [51]. Although a previous observational study showed that framing of recruitment information to emphasise uncertainty enhanced recruitment [52], when this was tested by the rigor of RCT methodology [49],[50], we found that framing did not appear to influence recruitment. Unexpectedly we found that the role of the recruiter also did not show evidence of influencing recruitment (although costs were higher for senior recruiters [28],[29]). In our review, one recruitment trial identified that a noninferiority clinical study (with active treatment arms) had higher consent rates compared with a placebo-controlled clinical study. This finding is consistent with previous findings that patients preferred “trials with all active arms to placebo-controlled trials” [53]. Also, recruitment trials that compared standard placebo-controlled design with a nonblinded trial design demonstrated that patients were more willing to participate in a clinical study if they knew which treatment they were receiving when consenting, even if the treatment was randomly predetermined. These studies illustrate people's anxieties regarding the unknowns of clinical trial participation. Despite the higher consent rates for the nonblinded trial design, the differential loss to follow up in the two treatments arms of the nonblinded trial is likely to jeopardise validity of the results, as comparison of outcomes between the two treatment groups would be subject to selection bias. For example, patients may be more likely to drop out if they were unhappy with the treatment they were assigned. In the two included studies of nonblinded trial designs, there were higher drop outs in the active treatment arms compared with the placebo arms. The inclusion of recruitment trials of recruitment to mock clinical studies enabled assessment of recruitment strategies, which for equity reasons would be difficult to compare (such as different randomisation designs, different monetary incentives). Some strategies may be acceptable when used in isolation, but inappropriate when more than one are used within the same clinical study: for example mock trials that tested the hypothesis that potential participants are more willing to participate in a study if they had an increased chance of receiving the experimental treatment is a strategy that has been adopted by many vaccine and other clinical studies in the belief that potential participants are more likely to participate if they believed they had a higher chance of receiving the (desirable) experimental treatment. However, we found that increasing the likelihood of receiving the experimental treatment [19] (or reducing the risk of receiving placebo) [14] did not appear to affect the consent rate, demonstrating that people's decisions for clinical study participation are not influenced by whether they are more or less likely to receive a particular treatment. Other strategies are more controversial: for example, the only consent strategy that appeared to affect the consent rate for a mock trial was “prerandomisation to standard drug” [18], where participants were given the standard drug and nonparticipants were given the experimental drug. Fewer people were willing to consent to this type of clinical study than to a clinical study of standard randomisation for all participants. It is unlikely that such a method could ethically be employed in a real situation. Monetary incentives appeared to increase consent compared to no monetary incentives [31], but the amount of money appeared to be less important [14]. As results of mock clinical studies are based on whether participants are willing to enrol in a clinical study (rather than whether they actually consented), extrapolation to real clinical studies may not be realistic. Stated “willingness to participate” and actual participation may also differ. In the recruitment trial comparing standard consent to the addition of a video explaining clinical trial information and the health problem studied for a mock clinical study, although statistically more participants from the video group were willing to enrol in the clinical study, this number became not statistically significant 2 wk later [44]. Conversely, in Sime's 1986 study [49], more participants actually consented to clinical study participation than had indicated willingness to participate, perhaps reflecting patients' deference to doctors' advice in the 1980s (when there was less emphasis on patient autonomy compared with today). It also showed the influence of the doctor on patient behaviour [53]. Although there have been two previous systematic reviews on strategies to enhance recruitment to research [9],[10], our study is the latest and has a more targeted and rigorous search method. We conducted a more comprehensive search (with inclusion of more databases than Watson's study [10]) and included earlier as well as later studies, and also studies of recruitment for mock trials to test recruitment strategies that would otherwise be difficult to compare for equity reasons. Our methods were also more rigorous (with two reviewers examining all titles, abstracts, and relevant papers) with an inclusion criteria targeting recruitment of participants for RCTs only (excluding studies about recruitment to observational studies, questionnaires, health promotional activities. and other health care interventions). We targeted recruitment to RCTs in which recruitment is more difficult because potential participants must consent to participation in research in which their treatment is unknown. The Mapstone study conducted in 2002 and published in 2007 [9] included recruitment for any type of research studies, and the Watson study [10], although targeting recruitment strategies used for RCTs, searched only from 1996 to 2004 with a limited number of electronic databases (without hand searching), using only the keywords “recruitment strategy” or “recruitment strategies.” Our study has identified more studies than the previous reviews (37 compared with 14 and 15 studies), and provides a better understanding of the factors that influence clinical RCT participation for potential participants. Although both previous studies highlighted effective and ineffective strategies, there was no attempt to examine the differences between successful and unsuccessful recruitment strategies. Our findings are consistent with the health belief model that people are more likely to adopt a health behaviour (such as participation in a clinical study) if they perceive they are at risk of a significant health problem [54]. The importance of informing potential participants about the health problem being studied and engaging them in the learning process is not only educational and constructive, but is also likely to enhance clinical trial participation. Limitations Because of major differences in recruitment methods, populations, and types of clinical studies that were recruiting as well as outcomes measured, we did not combine the results statistically in a meta-analysis. In many of the smaller recruitment trials, the failure to find a significant difference in consent rates could be related to the sample size (type II error). There may also be publication bias. However, as more than 70% (27/37) of the included studies had a nonsignificant result, we are hopeful that publication bias may be minimal. Given that the interventions we are considering are of noncommercial value we would suggest that publication bias may be less likely than for other interventions. The majority of the included trials were conducted in developed countries, with a substantial proportion in the US. We acknowledge that developed countries' health systems may be very different from those of less-developed countries and hence the results of this systematic review may not be generalizable to other countries. The main limitation of the study, due to the prolonged conduct of the study (from 2000 to 2009), was that the search strategy had to be modified with subsequent search updates owing to changes in MEDLINE Mesh heading definitions. Because of these changes (and the large number of titles and abstracts searched), the reason for exclusion of each study cannot be provided. The abstract of the first version of this systematic review (which included nonrandomised studies owing to the lack of randomised recruitment trials on the subject at the time) was published in conference proceedings in 2002 [11], and a later version that was limited to randomised studies was published in conference proceedings in 2007 [12]. Conclusion Our systematic review of recruitment strategies for enhancing participation in clinical RCTs has identified a number of effective and ineffective recruitment strategies. Grouped together, the statistically significant strategies either engaged participants in learning about the health problem being studied and its impact on their health or else informed participants of the treatment they have been randomised to receive (nonblinded trial design). However, as there was differential loss to follow up in the different treatment arms with nonblinded trial design, this trial design is likely to jeopardise the validity of the results. The use of monetary incentives may also increase recruitment, but as this was tested in a mock trial, and as another mock trial did not show any difference in consent rates between different amounts of monetary incentives, this finding needs to be interpreted with caution. Future RCTs of recruitment strategies that engaged participants in the learning process using various methods of delivering the recruitment material compared with standard recruitment may confirm the effectiveness of this concept. This research may be particularly useful for testing strategies that expose large number of potential participants to recruitment information such as interactive internet strategies. Supporting Information Text S1 PRISMA checklist. (0.07 MB DOC) Click here for additional data file.
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                Author and article information

                Contributors
                Journal
                Front Public Health
                Front Public Health
                Front. Public Health
                Frontiers in Public Health
                Frontiers Media S.A.
                2296-2565
                26 April 2019
                2019
                : 7
                : 104
                Affiliations
                [1] 1Interdisciplinary Gerontology Program, Department of Psychological Sciences, University of North Carolina at Charlotte , Charlotte, NC, United States
                [2] 2Meharry-Vanderbilt Alliance, Vanderbilt University Medical Center , Nashville, TN, United States
                [3] 3Sarah Cannon Research Institute, Sarah Cannon , Nashville, TN, United States
                [4] 4National Health Care for the Homeless Council , Nashville, TN, United States
                [5] 5Department of Medicine, Meharry Medical College , Nashville, TN, United States
                Author notes

                Edited by: John D. Carpten, University of Southern California, United States

                Reviewed by: Giridhara R. Babu, Public Health Foundation of India, India; Danice Brown Greer, University of Texas at Tyler, United States

                *Correspondence: Consuelo H. Wilkins consuelo.h.wilkins@ 123456meharry-vanderbilt.org

                This article was submitted to Epidemiology, a section of the journal Frontiers in Public Health

                †Deceased

                Article
                10.3389/fpubh.2019.00104
                6498183
                31106188
                caa3a4bf-99d3-4c6f-beff-03b2ef7937c7
                Copyright © 2019 Skinner, Fair, Holman, Boyer and Wilkins.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 January 2019
                : 10 April 2019
                Page count
                Figures: 2, Tables: 2, Equations: 0, References: 35, Pages: 7, Words: 4663
                Funding
                Funded by: Vanderbilt-Ingram Cancer Center 10.13039/100007208
                Funded by: National Center for Advancing Translational Sciences 10.13039/100006108
                Award ID: UL1 TR000445
                Categories
                Public Health
                Original Research

                clinical trials,ethnic groups,minority groups,patients,cancer,education,multimedia

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