|Year : 2021 | Volume
| Issue : 4 | Page : 642-646
Post hoc analysis of the screening log of phase III investigator-initiated randomized clinical trial comparing palliative oral metronomic versus intravenous chemotherapy in head-and-neck cancer
Sachin Dhumal1, Vijay Patil2, Vanita Noronha2, Amit Joshi2, Nandini Menon2, Kavita Nawale2, Rupali Tambe2, Kumar Prabhash2
1 Advanced Centre for Treatment Research and Education in Cancer (ACTREC), Kharghar, Navi Mumbai, India
2 Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
|Date of Submission||09-Jul-2021|
|Date of Decision||20-Oct-2021|
|Date of Acceptance||26-Nov-2021|
|Date of Web Publication||29-Dec-2021|
Room No. 1109, HBB, 11th Floor, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: Large number of screen failures in trials often result in delayed drug approvals, an increase in the financial burden for conducting research, and limit the applicability of the study results to patients in the clinic.
Objectives: This post hoc analysis was aimed at assessing the reasons for screen failures in a phase III, investigator-initiated clinical trial conducted in India.
Materials and Methods: The study was conducted at the Tata Memorial Center, a tertiary cancer center in Mumbai, India. We maintained a log of all potential study candidates who underwent screening in our outpatient department between May 2016 and January 2020. This included the name of the study subject, hospital registration number, age, and sex. We also recorded the screening date and outcome of the screening process (whether enrolled in the study and if not, the reason for it) along with the number of patients who were finally randomized in the study. We evaluated factors that may have impacted screen failure including age, sex, and performance status (PS).
Results: A total of 594 patients were screened. Of these, 422 were enrolled and 172 failed screening. Out of the 172 patients who were not enrolled, 105 (61%) did not meet the eligibility criteria and 67 (39%) refused to participate due to various reasons. The reasons for non-enrollment in the trial included the lack of a place to stay in Mumbai (35, 20.3%), patient wanted only a particular therapy (16, 9.3%), age over 70 years (15, 8.7%), poor PS (4, 2.3%), deranged organ function (13, 7.6%), active tuberculosis (2, 1.2%), primary tumor in the nasopharynx/thyroid/salivary gland/unknown primary (31, 18%), positivity for viral markers of infection (12, 7%), platinum-refractory disease (23, 13.4%), unwillingness to participate in research (15, 8.7%), patient not willing as they were not accompanied by a relative=1(0.06%) and other reasons (5, 2.9%). Age over 60 years (P = 0.001), and poor PS (P < 0.001) significantly increased the screen failure rate.
Conclusion: The most common cause for screen failures is the nonfulfillment of the eligibility criteria, followed by patient-related reasons such as unavailability of a place to stay at the trial location. Broadening the eligibility criteria to better reflect the patients most commonly seen in the clinic will function both to decrease the rate of screen failures and increase the applicability of the study results.
Keywords: Eligibility, head-and-neck cancer, palliative chemotherapy, screen failure, screening
|How to cite this article:|
Dhumal S, Patil V, Noronha V, Joshi A, Menon N, Nawale K, Tambe R, Prabhash K. Post hoc analysis of the screening log of phase III investigator-initiated randomized clinical trial comparing palliative oral metronomic versus intravenous chemotherapy in head-and-neck cancer. Cancer Res Stat Treat 2021;4:642-6
|How to cite this URL:|
Dhumal S, Patil V, Noronha V, Joshi A, Menon N, Nawale K, Tambe R, Prabhash K. Post hoc analysis of the screening log of phase III investigator-initiated randomized clinical trial comparing palliative oral metronomic versus intravenous chemotherapy in head-and-neck cancer. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jan 21];4:642-6. Available from: https://www.crstonline.com/text.asp?2021/4/4/642/334175
| Introduction|| |
Good clinical practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with GCP guidelines is essential in all clinical trials involving human subjects. According to Principle 2.6 of the International Conference on Harmonization-GCP, trials should be conducted in accordance with the Institutional Ethics Committee (IEC) approved protocol. Protocols describe the inclusion and exclusion criteria, which should be followed during the enrollment of subjects in the trial. Consolidated standards for reporting trials (CONSORT) is a statement that provides guidelines on reporting of randomized controlled clinical trials developed by the CONSORT Group. It recommends that a flow diagram for enrollment of subjects and the maintenance of screening data are necessary.,
In a retrospective study by Mahajan et al. conducted in patients with human epidermal growth factor receptor 2-positive breast cancer, the screen failure rate was 56.1% across 14 study sites. Another 5-year audit of clinical trials conducted at a tertiary care center in India reported that the screen failure rate was 5% due to abnormal laboratory values. In a pooled analysis of 12 qualitative studies by Mills et al., the common reasons for screen failure were complex and stringent eligibility criteria, fear of or lack of trust in the research, concern regarding potential side effects, the requirement for travel from a distant place, anxiety, poor social support, etc. In this study, we, therefore, aimed to assess the reasons for screen failure in a phase III investigator-initiated randomized clinical trial that has been published earlier.
| Materials and Methods|| |
General study details
This was a post hoc analysis of a phase III investigator-initiated randomized clinical trial comparing oral metronomic versus intravenous cisplatin in patients with recurrent, metastatic, or inoperable head-and-neck cancers, conducted in the outpatient department (OPD) of the Department of Medical Oncology at the Tata Memorial Hospital, a tertiary cancer center, in Mumbai, India from May 16, 2016, to January 17, 2020. The phase III trial was conducted according to the ethical guidelines outlined in the Declaration of Helsinki, GCP guidelines, and the Indian Council of Medical Research guidelines. The trial was approved by the (IEC-III Trial ID-900159) on July 6, 2015, and written informed consent was obtained from each participant before enrollment in the trial [Supplementary Appendix 1]. The trial was registered with the Clinical Trials Registry-India (CTRI/2015/11/006388) and was funded by the Tata Research Administrative Council of the Tata Memorial Hospital, Mumbai, India.
Participants enrolled in the trial had to have cytologically or pathologically proven squamous cell carcinoma of the head and neck and planned for palliative intent treatment for head-and-neck cancer. Patients enrolled could have distant metastases from a head-and-neck primary tumor, or recurrent head-and-neck cancers that were not amenable to curative surgery or irradiation (but had been treated adequately at initial diagnosis), or loco-regionally advanced disease deemed unsuitable for definitive surgery or radiotherapy; patients could receive palliative radiotherapy for symptomatic relief. Patients had to be between 18 and 70 years old and have an Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Patients had to have pretreatment normal hematological and biochemical parameters, including hemoglobin ≥8 mg/dL, absolute neutrophil count >1500 × 10e9/L, total leucocyte count >3000 × 10e9/L; platelet counts >100,000/mm3; creatinine clearance more than or equal to 45 ml/min; and, baseline liver function values within twice the normal limit for serum bilirubin. Patients had to be willing to provide written informed consent and be available for follow-up.
We excluded patients with a primary tumor in the thyroid or salivary gland or nasopharynx; patients with significant and uncontrolled comorbid conditions, for example, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and active tuberculosis; patients who had received cisplatin within the past 3 months; and patients with serological positivity for HIV, hepatitis B virus, or, hepatitis C virus.
The primary endpoint of the study was to determine the various reasons for screen failure and the factors influencing them. We aimed to assess whether factors such as age, sex, and PS influenced the rates of screen failure.
We maintained a log of all potential study candidates who underwent screening in the OPD between May 2016 and January 2020. The screening log was maintained in the form of an excel sheet and included information of the subjects' serial number, name, hospital registration number, age, sex, date, and outcome of the screening process (whether enrolled in the study and if not, the reason for ineligibility or refusal to participate). The screening log was maintained and updated daily by the coordinator assigned to the study and confidentiality was maintained so that only the designated study members, including the principal investigator and co-investigator, study coordinator, and research nurse, had access to it. We maintained a log of all subjects enrolled in the study, indicating their assigned study number.
The Statistical Package for the Social Sciences version 20 (IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY, USA: IBM Corp) was used for data analysis. Descriptive statistics were performed. Factors impacting participation in the trial were evaluated. The factors considered were age, sex, and PS. Age (18–59 vs. 60–70), sex, and PS were tested as categorical variables. Sex was evaluated as a potential factor that could impact participation in the trial due to the socio-cultural background of the country, which might have led to a gender bias towards cancer treatment. Fisher's exact test was used for analysis. A P < 0.05 was considered statistically significant. Details of the sample size calculation for the original study have been provided earlier. The sample size was not calculated for this analysis as this was a post hoc analysis of a randomized clinical trial; we included all patients who had failed screening.
| Results|| |
Between May 2016 and January 2020, a total of 594 subjects were screened, of which 172 failed screening and 422 were randomized in the trial [Figure 1]. Of the 172 patients who failed screening, 67 (39%) were not willing to participate and the remaining 105 (61%) did not fulfill the eligibility criteria.
[Table 1] shows the various reasons for ineligibility that led to screen failure in the trial. [Table 2] summarizes the patient-related factors that might have affected screen failure in the trial. Age >60 years (P = 0.001) and PS 2 (P < 0.001) were significantly associated with a higher chance of screen failure, while sex (P = 0.267) did not affect enrolment in the study.
| Discussion|| |
In our phase III, investigator-initiated, randomized clinical trial comparing palliative oral metronomic versus intravenous chemotherapy in patients with advanced head-and-neck cancer, the screen failure rate was approximately 29%. To the best of our knowledge, this is the first analysis of an investigator-initiated, randomized, phase III clinical trial in head-and-neck cancers in the palliative setting. We found that 39% of screen failures were because of patient refusal, while 61% were due to the fact that the patient did not meet the eligibility criteria. Our screen failure rate was similar to the 28.2% rate in the KEYNOTE 048 study (1228 patients screened and 882 enrolled). In contrast, the EXTREME study had a lower screen failure rate at 7.3% (477 patients screened and 442 enrolled). In an earlier study done by our group to evaluate the optimal regimen of concurrent cisplatin with radiation for locally advanced head-and-neck squamous cell carcinoma, the screen failure rate was much higher at 66.4% (892 patients screened and 300 enrolled). In the weekly-vs-3-weekly study, similar to our current study, the predominant reason for screen failure was the failure to meet the eligibility criteria in 78%; patient refusal constituted only 14.9%.
Maintaining a screening log is useful for investigators to assess for patient selection bias during enrollment. A meta-analysis by Wong et al. reported the screen failure rates in phase II/III clinical trials in genitourinary cancers. They analyzed the data of 50 published trials of genitourinary cancers conducted between 1996 and 2016; only 24 (48%) trials out of 50 had published the rates of screen failures. In another study by Mckane et al., the reasons for screen failure in a phase I oncology clinical trial were analyzed. It was observed that the screen failure rate increased when the patient had to travel a long distance for their treatment.
In our analysis, 61% of patients could not be enrolled because they did not meet the eligibility criteria and 39% of patients refused to participate. Another prospective study from our own center aimed to assess the accrual rate and reasons for the non-enrollment of patients with oral cancer in a clinical trial. The investigators reported that only 498 (37%) out of 1335 patients were enrolled in the trial, i.e., the screen failure rate was 62.7%. Of the 837 patients who were not enrolled, the reason for non-enrollment was patient-related in 655 (78%) and trial-related in 182 (22%). The most common patient-related reason for non-participation was a desire to avail treatment at the local place (26%). In our study, 35 (20.3%) out of 172 patients wanted to take part in the study, but due to logistic issues and the lack of a place to stay in Mumbai, they refused to participate.
Investigator-initiated studies are challenging to conduct because of the financial constraints and difficulties related to the management of the site and data management and analysis. A high rate of screen failure imposes a financial burden and delays the completion of the study, which in turn leads to delayed availability of new drugs and a delay in the release of practice-changing data for patients.,,,
In our study, 17.7% of the patients who had been screened did not meet the eligibility criteria as specified in the protocol of the study. Age, PS, and deranged organ function led to screen failures in 32 patients, i.e., 5.4% of the total patients screened. There were 8.7% of patients who were ineligible due to age over 70 years. Approximately 42% of cancer cases occur in older people above the age of 70 years, but in most of the oncology clinical trials including our own, older patients have been traditionally excluded. There should be adequate representation of older adults with cancer in clinical trials, as they constitute a significant proportion of the patients in the clinic in routine practice. The exclusion of older adults from clinical trials weakens the evidence for the use of investigational drugs in older patients and leads to confusion regarding the therapeutic efficacy and toxicity of investigational drugs. The recent policy statement from the American Society of Clinical Oncology and Friends of Cancer Research recommended the broadening of eligibility criteria to make clinical trials more representative. They advised relaxation of the restriction of eligibility due to various clauses such as prior washout periods, concomitant medications, prior therapies, laboratory reference ranges, and test intervals, and PS. There has been an increasing awareness of the need for trial data to be generalizable to people of all age groups, genders, and ethnicities. In our study almost one-third of the patients we evaluated were ineligible and this would affect the generalizability of the results of the study to all patients. We believe that analyzing the reasons for screen failure can help in the better management of trials in future.
Our study was limited by the fact that we performed a post hoc analysis of an investigator-initiated single-center phase III randomized study, hence the reasons for screen failures may not have been representative of a multicentric sponsored study in which patients are screened at multiple centers in different settings. In addition, although we documented the reasons for screen failure, we did not attempt to solve the issues like logistic difficulties, etc., Attempting to resolve these issues may have given us a better idea of whether intervention in terms of providing solutions, especially to logistic challenges could improve the trial recruitment rate.
| Conclusion|| |
In our study, the primary reason for screen failure was not fulfilling the eligibility criteria, followed by the patient-related reasons. Age, and PS impacted on the screen failure rate.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
Supplementary Appendix 1: Clinical Study Protocol
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