Audit of screen failure in 15 randomised studies from a low and middle-income country

Background Growth and development in patient management occurs via randomised studies. Screen failure is a significant hurdle while conducting randomised studies. There is limited data available from low and middle-income countries about factors resulting in screen failure. Hence, this audit was performed to identify the proportion of patients who screen failed and to elucidate reasons for the same. Methods This was an audit of 15 randomised studies performed by medical oncology solid tumour unit II of Tata Memorial Centre. The screening logs of these studies were acquired. From the screening logs, data regarding the number of patients who had screen failed & reason for the same were obtained. Descriptive statistics were performed. Results A total of 7,481 patients were screened for 15 randomised clinical studies. Out of these, 3,666 (49.0%) patients were enrolled into trials and 3,815 (51.0%) screen failed. The most common reason for screen failure was ‘not meeting inclusion criteria’ (54.9%) followed by declining to take treatment (22.2%). Other factors that affect enrolment were ‘not willing to stay in the locality of the trial site’ (6.2%), being recruited in other studies (3.7%), poor performance status (PS) (3.4%), non-compliance (2.2%), meeting exclusion criteria (0.9%) and ‘other’ (6.5%). Conclusion The commonest causes of screen failure in lower and middle-income countries are non-meeting of inclusion criteria followed by declining to take treatment, not willing to stay in locality of trial site, recruited into other studies, poor PS, non-compliance, meeting exclusion criteria & ‘other’. This information would help analysing and hence planning of newer strategies to decrease the rate of screen failure.


Introduction
Randomised clinical studies are fundamental to improvement and development in patient management. They help evaluate the efficacy of an existing or new intervention against standard of care or placebo hence offering valuable information on the relative benefit of the intervention. While a single study cannot provide conclusive evidence standalone, each such study helps lend credence to a hypothesis regarding the efficacy of an intervention, reduces bias and might provide additional data of idiosyncrasies in efficacy by disease type, severity, ethnicity, age, gender, etc. Thus, randomised clinical trials (RCTs) are often considered a robust way to determine the cause-effect relationship between an intervention and a given outcome [1].
Screen failure occurs when a patient is screened to be enrolled into a given study or trial but is unable to be enrolled. Screen failure is a significant hurdle while conducting randomised studies. Patients that are screened are already from a narrow set of patients deemed as potentially suitable for that trial and thus screen failure leads to a loss of valuable data in that trial. The power of a trial correlates inversely with the sample size and hence screen failure negatively impacts this. Screen failure also leads to a loss of valuable time and resources in the screening process which ultimately do not contribute towards the outcome result and often also in continued trial recruitment.
There is limited data available from low and middle income country (LMIC) about factors resulting in screen failure. Thus, we decided to perform this audit to try to identify the number of patients who underwent screen failure and attempt to elucidate reasons for the same.

Study conduct
This single-centre retrospective analysis was done at our institution in India. Fifteen RCTs that were performed at our institution were audited. The study was conducted in accordance with the standards laid down by the declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice (ICH-GCP) and Indian Council of Medical Research (ICMR). Data collection for the study was done in 2022.

Patient selection
Patients from 15 randomised studies done at our institution that underwent screen failure were selected for audit in this study. Screening was done by investigators in each study. Patients who were deemed as potential fits for each respective study underwent a screening procedure to determine enrolment into that study. If a patient was unable to be enrolled into the study for any given reason after being screened, they were classified as 'screen failure'. A flowchart of inclusion and exclusion criteria for patients in this study is depicted in Figure 1.

Data collection
The data was collected on a predefined data collection sheet which was shared with all investigators. The data collected was of the number of patients screened for each of the 15 trials, the number of patients who screen failed for each trial and the reason for their screen failure.

Results
A total 7,481 patients were screened for 15 randomised clinical studies. Out of these, 3,666 (49.0%) patients were enrolled into trial and 3,815 (51.0%) screen failed ( Table 1). Details of recruitment, intent and targeted site for each of the 15 studies are given in Table 2. Further details including the title as well as a 'key points' summary of each of these trials is included in Table S1 in the Supplementary Appendix. Total, enrolled and screenfailed patients by therapeutic site of trial and by intent of trial are depicted in Table 3 and 4 respectively. The most common reason for screen failure was non-meeting inclusion criteria (54.9%) followed by declining to take treatment (22.2%). These were followed by 'Other' (6.4%) which included reasons like taking a certain treatment at a different hospital or death before being able to complete screening. Not willing to stay at locality of trial site (6.2%), recruited in other study (3.7%) and poor performance status (PS) were the other significant causes for screen failure listed in order of magnitude. The full list of causes for screen failure is listed in Table 5 and in Figure 2.

Discussion
Randomised clinical studies are the cornerstone of advancement and development in patient management. They help evaluate the efficacy of an existing or new intervention against standard of care or placebo hence offering valuable information on the relative benefit of the intervention. RCTs are often considered a robust way to determine a cause-effect relationship between an intervention and a given outcome [1].
Screen failure occurs when a patient is screened to be enrolled into a given study or trial but is unable to be enrolled. Screen failure is a significant hurdle while conducting randomised studies [2].
Our data shows that the largest determinant of screen failure for patients is 'not meeting the inclusion criteria' (54.9%). While well-framed, objective criteria maintain the integrity of a study, this finding suggests that increasingly strict or rigid criteria could be contributing to a large number of screen failures [3,4]. Due to the burden of a large number of screen failures, it may be worth looking into and analysing inclusion criteria to ensure a balance between maintaining integrity of data and not being overly rigid [5][6][7].
Declining to participate in the trial (22.2%) and non-compliance (2.2%) made up a big part of screen failure. These are especially important determinants as they seem most amenable to correction [8,9]. To an extent, non-compliance of patients and also their decision against participating in the trial can benefit from better counselling and teaching methods by investigators involved in recruitment. Care should be taken to explain treatment options and regimens in a language that the patient understands and is comfortable with. The teach-back method can be used to ensure patient understanding. Involved personnel can undergo some training in counselling practices with the hope that it may lead to greater patient participation in trials.
The other criteria making a significant contribution that has room to be benefitted is 'unwillingness to stay in the locality of trial site' (6.2%). Treatment and trial participation often require regular treatment at short intervals and follow-up investigations at short intervals. Trials of this nature would require that the patient have ease of geographic access to the site of the trial on a daily or weekly basis. For some patients, the financial, logistical and social challenges of relocating to the trial site are a significant hurdle. Trials of relatively uncommon conditions designed with such accessibility requirements could have funding and provision allowing the relocation of a patient and their support to the site of the study temporarily. It could also provide basic necessities and/or a stipend, travel arrangement, concession, etc.
Screen failure has a detrimental effect on trial power because sample size and power are inversely correlated. Failure to pass a screening also wastes time and money that could have gone toward improving the outcome, and it frequently results in trial recruitment continuing [10,11].
There is limited data available from LMICs about factors resulting in screen failure. A similar audit coming out of a LMIC showed the screen failure rate at an impressive 5% [12,13].
Thus, we decided to perform this audit to try to identify the number of patients who underwent screen failure and attempt to elucidate reasons for the same.

Conclusion
This audit was performed as limited data exists on factors impacting screen failure in trials in LMICs. A total 7,481 patients were screened for 15 randomised clinical studies. Out of these, 3,666 (49.0%) patients were enrolled into trial and 3,815 (51.0%) screen failed. The most common reason of screen failure was non-meeting inclusion criteria (54.9%) followed by declining to take treatment (22.2%). This information would help analyse and hence planning of newer strategies to decrease the rate of screen failure.

Key findings
This audit was performed as limited data exists on factors impacting screen failure in trials in LMICs.
A total of 7,481 patients were screened for 15 randomised clinical studies. Out of these, 3,666 (49.0%) patients were enrolled into trial and 3,815 (51.0%) screen failed.
The most common reason of screen failure was non-meeting inclusion criteria (54.9%) followed by declining to take treatment (22.2%).
This information would help analyse and hence planning of newer strategies to decrease the rate of screen failure.

Conflicts of interest
None.  It was theorised that adding pemetrexed and carboplatin chemotherapy to an oral tyrosine kinase inhibitor may improve outcomes in EGFR-mutant advanced non-smallcell lung cancer (NSCLC). This was a phase III randomized trial in patients with advanced NSCLC harboring an EGFR-sensitizing mutation and a performance status of 0 to 2 who were planned to receive first-line palliative therapy. Between 2016 and 2018, 712 patients were screened, 362 patients screen failed and 350 patients were randomly assigned to Gef (n = 176) and Gef+C (n = 174). We aimed to find the optimal route of iron supplementation in patients with malignancy and iron deficiency (true or functional) anemia not receiving erythropoiesis stimulating agents (ESA). Adult patients with malignancy requiring chemotherapy, hemoglobin (Hb) <12 g/dL and serum ferritin <100 mcg/mL, transferrin saturation <20% or hypochromic red blood cells >10% were randomized to intravenous (IV) iron sucrose or oral ferrous sulfate. 749 patients were screened, 557 patients screen failed and 192 patients were enrolled.