|Year : 2015 | Volume
| Issue : 3 | Page : 139-143
Reporting of pre-enrolment screening with randomized clinical trials: A small item that could impact a big difference
Tiffany M Harris-Brown, David L Paterson
Department of Infection and Immunity Theme, The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, Queensland, Australia
|Date of Web Publication||6-Jul-2015|
Tiffany M Harris-Brown
The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, Queensland
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Introduction: Randomized controlled trials (RCTs), when conducted using ethical and transparent methods, become the ultimate standard for producing evidence-based knowledge in the field of medical research. We sought to determine the proportion of RCTs in which the number of screened patients is reported, and also to ascertain what predicted efficient screening (i.e., a high number of screened participants being enrolled). Materials and Methods: Thirty-five RCTs from the Journals Clinical Infectious Diseases and The Lancet Infectious Diseases were reviewed from the time period of January 2012 to July 2013 using standardised criteria. Results: From the 35 RCTs, 9 of 35 (26%) did not report the number of patients screened prior to recruitment. From the 26 studies that reported this screening figure, 10,215 (47%; range: 2-98%) of the screened participants (21,862) were subsequently enrolled. About 18.3% of those screened and not enrolled, met inclusion and exclusion criteria yet did not wish to participate in an RCT. Studies performed in developed countries and pediatric populations were more likely to have low rates of enrolment compared with the screened population although there was no statistical significance to these associations (P = 0.2 for both variables). Conclusion: Many reports of RCTs do not report screening figures, even though these add useful information about the feasibility of future trials.
Keywords: Clinical trials, enrolment, participant recruitment, randomized controlled trials, research methodology, screening
|How to cite this article:|
Harris-Brown TM, Paterson DL. Reporting of pre-enrolment screening with randomized clinical trials: A small item that could impact a big difference. Perspect Clin Res 2015;6:139-43
|How to cite this URL:|
Harris-Brown TM, Paterson DL. Reporting of pre-enrolment screening with randomized clinical trials: A small item that could impact a big difference. Perspect Clin Res [serial online] 2015 [cited 2020 Jul 15];6:139-43. Available from: http://www.picronline.org/text.asp?2015/6/3/139/159937
| Introduction|| |
The science and evidence-based knowledge provided by conducting and publishing a randomized controlled trial (RCT) in any clinical setting is vital to the advancement of theory and practice in that field. When RCTs are developed and reported in a clear, factual and ethical manner, they can become the gold standard when evaluating a clinical intervention.  Reporting on all aspects of the trial, from the preenrolment screening to the end data analysis of the indicated outcomes, should be seen as warranted information for providing a transparent trail for the reader and also for aiding in the development of subsequent future trials of a similar nature.
Information deemed essential when reporting on an RCT has been evaluated by many authors and has even reached an element of standardized requirement by organizations such as the International Committee of Medical Journal Editors,  and the World Health Organization through their trial registration minimum dataset.  The SPIRIT 2013 Statement,  an updated version of the original statement introduced in 2007, developed a checklist of recommended items that should be provided in a clinical trial's protocol and affiliated study documents. Within this checklist, the reporting of the investigator's strategies for recruitment and successfully achieving the targeted sample size is identified. Corresponding with a study's recruitment methodology is the initial identification of a preenrolment recruitment screening figure. Identifying how many potential participants were approached for recruitment prior to enrolment can provide the reader and future investigator with an essential level of detail, especially in resource-limited clinician-initiated trials.
In this article, we evaluate how often reporting of preenrolment recruitment screening figures occur and what role this can potentially play in determining a trial's success.
| Materials and methods|| |
Thirty-five RCTs were selected for review from the Journals Clinical Infectious Diseases and The Lancet Infectious Diseases from January 2012 to July 2013. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, These two journals were selected for review for their high-impact factor and level of academic preeminence within the field of infectious diseases. A review of each journal's archive database starting from most recent was performed to identify these RCTs. The only search criteria used was to identify solely published RCTs from these two journals within the demonstrated timeframe.
Through each article's review, the primary aim was to evaluate preenrolment screening. We asked two questions: (1) Was the number of screened patients reported in the study results?; and (2) what predicted a high proportion of screened patients being enrolled?
Firstly, studies were identified as to whether or not a preenrolment screening figure was reported either within the methods/results or an illustrated flow diagram figure. From this given figure a percentage was calculated for each trial to demonstrate what number of participants were enrolled from those that had been screened, and what percentage were excluded. Next, reasons for exclusion from enrolment post-screening were identified. These reasons were further broken down into the categories of: "did not meet inclusion criteria," "met exclusion criteria", or "other." The reasons for exclusion that were identified as "other" were further reviewed if provided by the article.
Additional variables were also evaluated. Each of the 35 articles that were reviewed discussed a range of infectious diseases topics from human immunodeficiency virus (HIV), hepatitis C virus (HCV), respiratory tract infections (RTIs) to antimicrobial prophylaxis. The trials assessed exemplified characteristics of both paediatric (≤18 years of age) and adult populations, pharmaceutical and nonpharmaceutical support, and geographic diversity within the United States (US), non-US countries and combined international collaborations. The variable of the trial being conducted in a developed versus a developing setting was also evaluated, with the classifications modelling those provided by The World Bank. 
Variables associated with "efficient" rates of enrolment compared to the screened population (arbitrarily defined as >75% of those screened were enrolled) were assessed using the Fisher's exact test.
| Results|| |
In total 57,400 (mean: 1640 and range: 48-43,802) participants were enrolled across the 35 RCTs. A range of subject areas were discussed throughout the studies: (20%) HIV, (17%) tropical diseases, (14%) vaccines, (11%) HCV, (6% each) for sexually transmitted infections, RTIs, skin and fungal infections, and (3% each) for sepsis, urinary tract and viral infections, Clostridium difficile infections, and prophylaxis treatments. Studies whose participant age criteria were adults (≥18 years of age) accounted for 23 of 35 (66%) and pharmaceutical supported studies accounted for 19 of 35 (54%). The most prevalent geographic location was studies conducted solely in non-US countries, 20 of 35 (57%), with international combined (including US) representing 8 of 35 (23%) and US only accounting for 7 of 35 (20%). The studies conducted in developed settings 25 of 35 (71%), out-numbered those performed in developing settings.  The mean duration of study length among the 35 trials was 26 months (range 1.2-84 months).
From these studies, 9 of 35 (26%) did not provide a preenrolment and randomization recruitment screening figure. Within the 26 studies that did report a recruitment screening figure, 21,862 (mean: 841, and range: 74-6491) participants were screened and 10,215 (mean: 393 and range: 48-2061) were subsequently enrolled. The percentage of participants that were successfully enrolled from those screened was calculated for each of the 26 studies that provided a screened figure. From the 26 studies that provided a recruitment screening figure, 47% (range: 2-98%) of participants were enrolled. Exclusion figures and criteria were analyzed for those 26 studies that reported reasons for screened individuals not being enrolled. Rationale for nonenrolment was largely represented by screened participants not meeting all inclusion or exclusion criteria 8858 (40.5%) or "declined or refused to participate" 2135 (9.77% of all of those who were screened, but not enrolled).
From these 26 studies, 5 of 26 (19%) achieved <50% enrolment from participants who were screened, with 1 of the 5 studies achieving <10% enrolment from recruitment screening. Common factors identified from these studies were all 5 had non-pharmaceutical involvement, 4 of 5 (80%) were paediatric populations, along with the same percentage being represented for studies occurring in non-USA locations.
The results in [Table 1] demonstrate the variables that contributed to "efficient" enrolment, arbitrarily defined as >75% success in enrolment throughout the 26 studies. No variables significantly predicted "efficient" enrolment, although studies performed in developed countries and with pediatric populations were less likely to exceed >75% success in enrolment.
|Table 1: Predictors of enrolment in RCTs (efficient enrollers defined as >75% screened patients enrolled in the study) |
Click here to view
| Discussion|| |
Recruitment is invariably an issue that requires attention within clinical trials. Many times investigators are faced with needing to re-visit and adjust a study's initial participant recruitment strategies. Difficulties with maintaining a study's timeline because of recruitment barriers can gravely jeopardise a study's financial and physical resources along with delaying the availability of its potentially beneficial outcomes.
Reporting accurate participant recruitment and retainment figures, including those screened, enrolled and reasons for exclusion, are an essential component of performing clinical research. Yet we found that 9 of 35 (26%) RCTs published in high-impact infectious diseases journals did not demonstrate a preenrolment and randomization recruitment screening figure. These elements should be reported because they allow for a trial's infrastructure to be clearly visualized from commencement to final analysis. Any steps that will provide a clearer translation and greater knowledge-base of clinical research practices are valuable and essential to the future of health research.
We did not find statistically significant variables that predicted suboptimal enrolment to screening ratios, although there were trends to lower recruitment rates in developed countries and pediatric populations. Addressing recruitment strategies through conducting a pilot study can prove beneficial by identifying factors that may have gone undetected during a study's protocol development. One identified study looked at recruitment strategies when pilot studies were conducted in RCT's, and found that over 50% of the trials had to perform changes to their recruitment strategies and protocols because of issues highlighted during the formal pilot study. Having to modify study documents, inclusion criteria, sample sizes and adding additional study sites were commonly adjusted items that were identified from performing these pilot studies. 
When a clinical trial runs into unexpected recruitment and enrolment issues, maintaining momentum and the trial team's sense of ownership can be challenging. Poor recruitment, when met with financial and physical resource strain, can contribute to a decrease in trial staff morale and achieving expected outcomes. Developing the practice of documenting and identifying a preenrolment screening figure and associated exclusion reasons, especially when a formal pilot study is not performed, can aid investigators with determining a trial's shortfalls along with future recruitment predictions for trials of a similar nature.
Louis Lasagna, an American clinical pharmacologist, coined the theory of "Lasagna's law" observing that at the moment a trial's recruitment begins, the availability of suitable participants to recruit sharply decreases from what was assumed prior to the trial's commencement.  This theory could be interpreted however, as challenging the guidelines for good clinical practice set by the International Conference on Harmonisation (ICH), "4.2.1 - The investigator should be able to demonstrate (e.g., based on retrospective data) a potential for recruiting the required number of suitable subjects within the agreed recruitment period". 
When underestimated barriers to recruitment are faced, severe consequences in the form of premature ethical termination and refusal of grant extensions can occur. We advocate careful consideration of barriers to recruitment in all trials, and publication of numbers both screened and enrolled in order to better understand all clinical trials.
| Acknowledgment|| |
DLP - has received honoraria from AstraZeneca, Merck and Pfizer.
| References|| |
Schulz KF, Altman DG, Moher D, Group C. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152:726-32.
Laine C, Horton R, DeAngelis CD, Drazen JM, Frizelle FA, Godlee F, et al.
Clinical trial registration - Looking back and moving ahead. N Engl J Med 2007;356:2734-6.
Moja LP, Moschetti I, Nurbhai M, Compagnoni A, Liberati A, Grimshaw JM, et al.
Compliance of clinical trial registries with the World Health Organization minimum data set: A survey. Trials 2009;10:56.
Chan AW, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jeric K, et al.
SPIRIT 2013 statement: Defining standard protocol items for clinical trials. Ann Intern Med 2013;158:200-7.
Pallin DJ, Binder WD, Allen MB, Lederman M, Parmar S, Filbin MR, et al.
Clinical trial: Comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: A randomized controlled trial. Clin Infect Dis 2013;56:1754-62.
Mand S, Debrah AY, Klarmann U, Batsa L, Marfo-Debrekyei Y, Kwarteng A, et al.
Doxycycline improves filarial lymphedema independent of active filarial infection: A randomized controlled trial. Clin Infect Dis 2012;55:621-30.
Basra A, Mombo-Ngoma G, Melser MC, Diop DA, Würbel H, Mackanga JR, et al.
Efficacy of mefloquine intermittent preventive treatment in pregnancy against Schistosoma haematobium
infection in Gabon: A nested randomized controlled assessor-blinded clinical trial. Clin Infect Dis 2013;56:e68-75.
Cowling BJ, Ng S, Ma ES, Fang VJ, So HC, Wai W, et al.
Protective efficacy against pandemic influenza of seasonal influenza vaccination in children in Hong Kong: A randomized controlled trial. Clin Infect Dis 2012;55:695-702.
Tam DT, Ngoc TV, Tien NT, Kieu NT, Thuy TT, Thanh LT, et al.
Effects of short-course oral corticosteroid therapy in early dengue infection in Vietnamese patients: A randomized, placebo-controlled trial. Clin Infect Dis 2012;55:1216-24.
Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, et al.
Continuous infusion of beta-lactam antibiotics in severe sepsis: A multicenter double-blind, randomized controlled trial. Clin Infect Dis 2013;56:236-44.
Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, et al.
Linezolid in methicillin-resistant Staphylococcus aureus
nosocomial pneumonia: A randomized, controlled study. Clin Infect Dis 2012;54:621-9.
Salo J, Uhari M, Helminen M, Korppi M, Nieminen T, Pokka T, et al.
Cranberry juice for the prevention of recurrences of urinary tract infections in children: A randomized placebo-controlled trial. Clin Infect Dis 2012;54:340-6.
Fritz SA, Hogan PG, Hayek G, Eisenstein KA, Rodriguez M, Epplin EK, et al.
Household versus individual approaches to eradication of community-associated Staphylococcus aureus
in children: A randomized trial. Clin Infect Dis 2012;54:743-51.
Aurelius E, Franzen-Röhl E, Glimåker M, Akre O, Grillner L, Jorup-Rönström C, et al.
Long-term valacyclovir suppressive treatment after herpes simplex virus type 2 meningitis: A double-blind, randomized controlled trial. Clin Infect Dis 2012;54:1304-13.
Havens PL, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, et al.
Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: A randomized, placebo-controlled trial. Clin Infect Dis 2012;54:1013-25.
Turner RB, Fuls JL, Rodgers ND, Goldfarb HB, Lockhart LK, Aust LB. A randomized trial of the efficacy of hand disinfection for prevention of rhinovirus infection. Clin Infect Dis 2012;54:1422-6.
Valecha N, Krudsood S, Tangpukdee N, Mohanty S, Sharma SK, Tyagi PK, et al.
Arterolane maleate plus piperaquine phosphate for treatment of uncomplicated Plasmodium falciparum
malaria: A comparative, multicenter, randomized clinical trial. Clin Infect Dis 2012;55:663-71.
Park WB, Kim NH, Kim KH, Lee SH, Nam WS, Yoon SH, et al.
The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: A randomized controlled trial. Clin Infect Dis 2012;55:1080-7.
Geisler WM, Koltun WD, Abdelsayed N, Burigo J, Mena L, Taylor SN, et al.
Safety and efficacy of WC2031 versus vibramycin for the treatment of uncomplicated urogenital Chlamydia trachomatis
infection: A randomized, double-blind, double-dummy, active-controlled, multicenter trial. Clin Infect Dis 2012;55:82-8.
van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al.
Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: Planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis 2012;12:111-8.
Phiri K, Esan M, van Hensbroek MB, Khairallah C, Faragher B, ter Kuile FO. Intermittent preventive therapy for malaria with monthly artemether-lumefantrine for the post-discharge management of severe anaemia in children aged 4-59 months in southern Malawi: A multicentre, randomised, placebo-controlled trial. Lancet Infect Dis 2012;12:191-200.
Pol S, Ghalib RH, Rustgi VK, Martorell C, Everson GT, Tatum HA, et al.
Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: A randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial. Lancet Infect Dis 2012;12:671-7.
Richmond PC, Marshall HS, Nissen MD, Jiang Q, Jansen KU, Garcés-Sánchez M, et al.
Safety, immunogenicity, and tolerability of meningococcal serogroup B bivalent recombinant lipoprotein 2086 vaccine in healthy adolescents: A randomised, single-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 2012;12:597-607.
Kharfan-Dabaja MA, Boeckh M, Wilck MB, Langston AA, Chu AH, Wloch MK, et al.
A novel therapeutic cytomegalovirus DNA vaccine in allogeneic haemopoietic stem-cell transplantation: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Infect Dis 2012;12:290-9.
Cornely OA, Crook DW, Esposito R, Poirier A, Somero MS, Weiss K, et al.
Fidaxomicin versus vancomycin for infection with Clostridium difficile
in Europe, Canada, and the USA: A double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis 2012;12:281-9.
Imamura H, Kurokawa Y, Tsujinaka T, Inoue K, Kimura Y, Iijima S, et al.
Intraoperative versus extended antimicrobial prophylaxis after gastric cancer surgery: A phase 3, open-label, randomised controlled, non-inferiority trial. Lancet Infect Dis 2012;12:381-7.
Puthanakit T, Saphonn V, Ananworanich J, Kosalaraksa P, Hansudewechakul R, Vibol U, et al.
Early versus deferred antiretroviral therapy for children older than 1 year infected with HIV (PREDICT): A multicentre, randomised, open-label trial. Lancet Infect Dis 2012;12:933-41.
Reynolds SJ, Makumbi F, Newell K, Kiwanuka N, Ssebbowa P, Mondo G, et al.
Effect of daily aciclovir on HIV disease progression in individuals in Rakai, Uganda, co-infected with HIV-1 and herpes simplex virus type 2: A randomised, double-blind placebo-controlled trial. Lancet Infect Dis 2012;12:441-8.
Walson J, Singa B, Sangaré L, Naulikha J, Piper B, Richardson B, et al.
Empiric deworming to delay HIV disease progression in adults with HIV who are ineligible for initiation of antiretroviral treatment (the HEAT study): A multi-site, randomised trial. Lancet Infect Dis 2012;12:925-32.
Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, et al.
Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: An open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013;13:27-35.
Little P, Stuart B, Moore M, Coenen S, Butler CC, Godycki-Cwirko M, et al.
Amoxicillin for acute lower-respiratory-tract infection in primary care when pneumonia is not suspected: A 12-country, randomised, placebo-controlled trial. Lancet Infect Dis 2013;13:123-9.
Gurwith M, Lock M, Taylor EM, Ishioka G, Alexander J, Mayall T, et al.
Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: A randomised, double-blind, placebo-controlled, phase 1 study. Lancet Infect Dis 2013;13:238-50.
Bonnet M, Bhatt N, Baudin E, Silva C, Michon C, Taburet AM, et al.
Nevirapine versus efavirenz for patients co-infected with HIV and tuberculosis: A randomised non-inferiority trial. Lancet Infect Dis 2013;13:303-12.
Deterding K, Grüner N, Buggisch P, Wiegand J, Galle PR, Spengler U, et al.
Delayed versus immediate treatment for patients with acute hepatitis C: A randomised controlled non-inferiority trial. Lancet Infect Dis 2013;13:497-506.
Sulkowski M, Pol S, Mallolas J, Fainboim H, Cooper C, Slim J, et al.
Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: A randomised, double-blind, controlled phase 2 trial. Lancet Infect Dis 2013;13:597-605.
Molina JM, Lamarca A, Andrade-Villanueva J, Clotet B, Clumeck N, Liu YP, et al.
Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: Randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis 2012;12:27-35.
McElhaney JE, Beran J, Devaster JM, Esen M, Launay O, Leroux-Roels G, et al.
AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: A phase 3 randomised trial. Lancet Infect Dis 2013;13:485-96.
Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al.
Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: A randomised, double-blind, phase 2 trial. Lancet Infect Dis 2013;13:401-8.
Morrissey CO, Chen SC, Sorrell TC, Milliken S, Bardy PG, Bradstock KF, et al.
Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: A randomised controlled trial. Lancet Infect Dis 2013;13:519-28.
The World Bank. Country Classifications and Lending Groups; 2013. Available from: http://www.data.worldbank.org/about/country-classifications/country-and-lending-groups#Upper_middle_income. [Last cited on 2013 Sep 15].
McDonald AM, Knight RC, Campbell MK, Entwistle VA, Grant AM, Cook JA, et al.
What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies. Trials 2006;7:9.
van der Wouden JC, Blankenstein AH, Huibers MJ, van der Windt DA, Stalman WA, Verhagen AP. Survey among 78 studies showed that Lasagna's law holds in Dutch primary care research. J Clin Epidemiol 2007;60:819-24.
The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). (1996) ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R1), 1-59. p. 13. Available from: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R1_Guideline.pdf. [Last accessed on 2014 Nov 05].