Letter: Enrollment-To-Screening Ratio: An Undervalued Data in Randomized Clinical Trials

Letter: Enrollment-To-Screening Ratio: An Undervalued Data in Randomized Clinical Trials To the Editor: Randomized clinical trials (RCTs) are considered the gold standard for evaluating the safety and efficacy of new medications, medical devices, and surgical procedures.1,2 The conduct of these trials produces evidence-based knowledge intended to translate into changes in clinical practice. Overall, RCTs can shape the development of new treatments, satisfying the constant need for improvement in health care. Screening tests are an integral part of RCTs and are aimed at prospectively evaluating persons to identify eligible candidates. We report our institutional experience as a recruitment site for the MISTIE-II trial (Minimally Invasive Surgery Plus rt-PA [recombinant tissue plasminogen activator] for ICH [intracerebral hemorrhage] Evacuation Phase III (ClinicalTrials.gov Identifier: NCT01827046). For this randomized, case-controlled, open-label, phase III study, 740 patients at our institution were screened from December 2013 to January 2017, but only 6 patients were ultimately enrolled. Several factors may contribute to the ineligibility of patients. In most cases, strict inclusion criteria and strict exclusion criteria lead to ineligibility. In rare instances, patients withdraw consent before starting the medical intervention under investigation or give consent for participation in a different experimental trial that is incompatible with the one in which they were originally enrolled. Adequate screening is necessary to achieve the desired recruitment goal, and satisfying enrollment goals is a prerequisite to obtain study results that will potentially be statistically significant. An insufficient number of participants leads to the failure of a clinical trial. The major implications of this scenario are the considerable delay to the expected completion of the study, the added financial burden on its sponsors, and the deferral of potential benefits from the early availability of study results.3 Despite the lack of consensus about the optimal enrollment-to-screening ratio, one group of authors has arbitrarily proposed >75:100 (>75% of those screened were enrolled) as an “efficient” rate of enrollment.3 However, data in the medical literature that support such a rate are suboptimal. One investigation of a cohort of multicenter trials funded through 2 agencies in the United Kingdom to recruit participants between 1994 and 2002 found that only 31% (n = 38) of 114 studies achieved their original recruitment target, whereas 53% of 114 required an enrollment extension.4 No statistically significant factors have been associated with a lower recruitment rate, although it tends to be more common in pediatric studies and in studies conducted in developed countries.3 Given the importance of the recruitment phase of a clinical trial, we believe that the role of pre-enrollment screening should not be underestimated and that proper recruitment strategies should be adopted to avoid slow recruitment and under-recruitment. The use of a pilot study might help address these recruitment issues. A feasibility study that is conducted in a small group of persons before the start of an RCT can often reveal flaws in the protocol and provide an opportunity for them to be corrected. These pilot studies may also contribute by identifying more variables of interest and additional limiting factors that were overlooked during the development of the original study protocol.3 Thus, they enable investigators to selectively refine the design of the RCT. Another method for overcoming recruitment challenges would be to conduct an analysis of the comprehensive enrollment outcomes of RCTs in published reports. Recruitment data from previous studies could effectively guide investigators to improve ongoing and future trials. However, up to 26% of published reports about RCT fail to indicate the number of patients who underwent the initial clinical screening prior to recruitment.3 The remarkable lack of these data significantly jeopardizes the integrity of any enrollment-to-screening ratio based on the available literature. We plan to further analyze our data to help elucidate the reasons for the extremely low enrollment ratio (6:740) in the MISTIE-III trial at our institution. We strongly support the interests and intent of the principal investigators who designed the overall MISTIE trial. However, a modicum of doubt limits the general applicability of the results of any RCT with an enrollment-to-screening ratio of <1:100. Prospective analyses are thus needed to develop and implement strategies that will lead to a more successful recruitment phase. Likewise, the use of more targeted pilot studies and consolidated reporting standards regarding pre-enrollment screening should be beneficial to the design of more effective study protocols. Such methods could optimize the enrollment-to-screening ratio of RCTs and have a consequentially positive effect on their financial and physical resources. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Bowling A . Investigating health and health services . Research Methods in Health . 2nd ed . Philadelphia, PA : Open University Press ; 2002 . 2. Pocock S . A practical approach . Clinical Trials . Chichester : Wiley and Sons Ltd .; 1983 : 278 . 3. 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 ( 3 ): 139 - 143 . Google Scholar CrossRef Search ADS PubMed 4. McDonald AM , Knight RC , Campbell MK et al. What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies . Trials . 2006 ; 7 ( 1 ): 9 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Letter: Enrollment-To-Screening Ratio: An Undervalued Data in Randomized Clinical Trials

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Publisher
Oxford University Press
Copyright
Copyright © 2018 by the Congress of Neurological Surgeons
ISSN
0148-396X
eISSN
1524-4040
D.O.I.
10.1093/neuros/nyy079
Publisher site
See Article on Publisher Site

Abstract

To the Editor: Randomized clinical trials (RCTs) are considered the gold standard for evaluating the safety and efficacy of new medications, medical devices, and surgical procedures.1,2 The conduct of these trials produces evidence-based knowledge intended to translate into changes in clinical practice. Overall, RCTs can shape the development of new treatments, satisfying the constant need for improvement in health care. Screening tests are an integral part of RCTs and are aimed at prospectively evaluating persons to identify eligible candidates. We report our institutional experience as a recruitment site for the MISTIE-II trial (Minimally Invasive Surgery Plus rt-PA [recombinant tissue plasminogen activator] for ICH [intracerebral hemorrhage] Evacuation Phase III (ClinicalTrials.gov Identifier: NCT01827046). For this randomized, case-controlled, open-label, phase III study, 740 patients at our institution were screened from December 2013 to January 2017, but only 6 patients were ultimately enrolled. Several factors may contribute to the ineligibility of patients. In most cases, strict inclusion criteria and strict exclusion criteria lead to ineligibility. In rare instances, patients withdraw consent before starting the medical intervention under investigation or give consent for participation in a different experimental trial that is incompatible with the one in which they were originally enrolled. Adequate screening is necessary to achieve the desired recruitment goal, and satisfying enrollment goals is a prerequisite to obtain study results that will potentially be statistically significant. An insufficient number of participants leads to the failure of a clinical trial. The major implications of this scenario are the considerable delay to the expected completion of the study, the added financial burden on its sponsors, and the deferral of potential benefits from the early availability of study results.3 Despite the lack of consensus about the optimal enrollment-to-screening ratio, one group of authors has arbitrarily proposed >75:100 (>75% of those screened were enrolled) as an “efficient” rate of enrollment.3 However, data in the medical literature that support such a rate are suboptimal. One investigation of a cohort of multicenter trials funded through 2 agencies in the United Kingdom to recruit participants between 1994 and 2002 found that only 31% (n = 38) of 114 studies achieved their original recruitment target, whereas 53% of 114 required an enrollment extension.4 No statistically significant factors have been associated with a lower recruitment rate, although it tends to be more common in pediatric studies and in studies conducted in developed countries.3 Given the importance of the recruitment phase of a clinical trial, we believe that the role of pre-enrollment screening should not be underestimated and that proper recruitment strategies should be adopted to avoid slow recruitment and under-recruitment. The use of a pilot study might help address these recruitment issues. A feasibility study that is conducted in a small group of persons before the start of an RCT can often reveal flaws in the protocol and provide an opportunity for them to be corrected. These pilot studies may also contribute by identifying more variables of interest and additional limiting factors that were overlooked during the development of the original study protocol.3 Thus, they enable investigators to selectively refine the design of the RCT. Another method for overcoming recruitment challenges would be to conduct an analysis of the comprehensive enrollment outcomes of RCTs in published reports. Recruitment data from previous studies could effectively guide investigators to improve ongoing and future trials. However, up to 26% of published reports about RCT fail to indicate the number of patients who underwent the initial clinical screening prior to recruitment.3 The remarkable lack of these data significantly jeopardizes the integrity of any enrollment-to-screening ratio based on the available literature. We plan to further analyze our data to help elucidate the reasons for the extremely low enrollment ratio (6:740) in the MISTIE-III trial at our institution. We strongly support the interests and intent of the principal investigators who designed the overall MISTIE trial. However, a modicum of doubt limits the general applicability of the results of any RCT with an enrollment-to-screening ratio of <1:100. Prospective analyses are thus needed to develop and implement strategies that will lead to a more successful recruitment phase. Likewise, the use of more targeted pilot studies and consolidated reporting standards regarding pre-enrollment screening should be beneficial to the design of more effective study protocols. Such methods could optimize the enrollment-to-screening ratio of RCTs and have a consequentially positive effect on their financial and physical resources. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. Bowling A . Investigating health and health services . Research Methods in Health . 2nd ed . Philadelphia, PA : Open University Press ; 2002 . 2. Pocock S . A practical approach . Clinical Trials . Chichester : Wiley and Sons Ltd .; 1983 : 278 . 3. 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 ( 3 ): 139 - 143 . Google Scholar CrossRef Search ADS PubMed 4. McDonald AM , Knight RC , Campbell MK et al. What influences recruitment to randomised controlled trials? A review of trials funded by two UK funding agencies . Trials . 2006 ; 7 ( 1 ): 9 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: May 8, 2018

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