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Journal of Clinical Oncology, Vol 24, No 6 (February 20), 2006: pp. 843-845 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.6005
The Importance of Reporting Patient Recruitment Details in Phase III Trials
1 Juravinski Cancer Centre at Hamilton Health Sciences, and Department of Medicine, McMaster University, Hamilton, ON, Canada The critical assessment of a reported phase III clinical trial requires an appreciation for two key methodological criteria. The internal validity of the trial relates to whether the study results are likely to be true and unbiased. The external validity, more commonly referred to as the generalizability of a trial result, relates to whether the study patients were similar to those patients in one’s own practice for whom the results may be applicable. For the generalizability of a phase III trial to be determined, details of the study population and the larger target population from which they were recruited must be provided.1 The process of identifying a target population, reviewing eligibility criteria, and obtaining consent to assemble a study population has been referred to as the recruitment process.2 The steps in the recruitment process are best appreciated when the target population of interest, or the potentially eligible patients, are described by a limited number of broad inclusion criteria. In distinction, exclusion criteria should then refine the population of interest, or act as supplements to the main definition, to exclude patients unsuitable for the trial and to deal with safety and regulatory issues.3 Eligible patients are then defined as those potentially eligible patients that do not meet any exclusion criteria of the trial. This distinction in criteria, inclusion versus exclusion, is lost when statements are arbitrarily framed as positive or negative, or when opposed versions of the same statement appear as one of each. Appreciating inclusion and exclusion criteria in this context, Gross et al have suggested three summary measures to describe the recruitment process: the "eligibility fraction" is the ratio of eligible/potentially eligible patients; the "enrollment fraction" is the ratio of enrolled/eligible patients; and the "recruitment fraction" is a summary statistic representing the product of the two ratios, or the ratio of enrolled/potentially eligible patients (see Fig 1 of Gross et al).2
The Consolidated Standards for Reporting Trials (CONSORT) guidelines were developed to improve the suboptimal reporting of phase III trials. The original CONSORT statement suggested that eligibility criteria be outlined, without the need to categorize whether such criteria are labeled as inclusion or exclusion in nature. It did not deal directly with the issue of reporting the recruitment process.4 However a more recent revision of the CONSORT guidelines suggests that authors discuss the generalizability of the trial results and include the number of potentially eligible patients assessed for eligibility.5 Beyond the importance of generalizability, the details of the recruitment process are also relevant to those with an interest in optimizing patient recruitment to clinical trials. Measures of the recruitment process through the course of a trial could provide valuable information to help identify key obstacles to accrual, such as too few patients with the stage of disease of interest; too few patients being identified or approached; too restrictive exclusion criteria; or poor acceptance by patients. Directed amendments to the study design could then be implemented to improve accrual. The details of the recruitment process in medicine trials remain infrequently reported, with estimates of up to 47% in cohorts of primary reports.2 To obtain a snapshot of this occurrence in the cancer literature, we conducted a limited review of the phase III trials published in 2003. A literature search using PubMed was performed for published reports from January 1 to December 31, 2003, indexed with: "neoplasms-drug therapy," or "neoplasms-therapy," or "neoplasms-radiotherapy," all as major subject headings; "randomized controlled trial" as publication type; human; and English language. Initially, titles and abstracts were reviewed, then full articles of interest were sorted by journal, and those with more than five published reports were deemed the most active sources of oncology trials. One hundred thirty primary reports from the eight most active journals (> five reports) were reviewed in detail, of which 18 were thought to represent secondary analyses of previously reported trials or phase II trials, such that there were a total of 112 primary reports of phase III clinical trials. Of these 112 reports, we found only two that provided detailed measures of the patient recruitment process (Table 1).
The most complete example was published by Ando et al, who reported the results of a clinical trial comparing surgery alone versus surgery followed by chemotherapy for patients with squamous cell carcinoma of the thoracic esophagus.6 It was reported that 2,403 patients underwent resection of esophageal cancer at the participating institutions during the study period, and that 511 patients met all eligibility criteria (an eligibility fraction of 21%), of which 242 consented to trial entry (an enrollment fraction of 47%). This resulted in an overall recruitment fraction of 10% (see Fig 2 of Ando et al). The reasons why so many patients failed to meet the eligibility requirements were not described.
The second trial, published by Malmstrom et al, evaluated radiation therapy after breast conserving surgery.7 They reported that in South and West Sweden, 31% of all women who fit nodal status, tumor size, and age criteria were included in their trial. While 31% represents the overall recruitment fraction of the trial, the details required to determine the eligibility fraction (eligible/potentially eligible) and the enrollment fraction (enrolled/eligible) were not provided. As most clinical trials reported in 2003 began many years before the revised CONSORT statement, these findings may not be surprising. While the quantitative aspects of these revised recommendations were followed in only two of these 112 reports, seven authors have reported the generalizability of their trial results from a qualitative perspective.8-14 Ideally authors should report details of the recruitment process collectively from all involved centers over the course of the trial, minimally to include the number of patients that met the inclusion criteria; the number of patients excluded and the reasons why; and the number of patients who accepted participation and were enrolled. This requires well-developed inclusion and exclusion criteria as outlined previously. When the patients not in the trial are sufficiently described, clinicians could decide whether the differences are likely to affect the treatment effect reported in the trial.15,16 In a highly selected trial population, the question of generalizability becomes: how useful are the results of such a study in a more typical population of patients? Unfortunately such information is rarely reported, and oncologists and patients are left estimating how selected the trial population is and what implications it may have for applying the results of the trial in practice. Although poor accrual to clinical trials is recognized as a concern to patients and oncologists alike, our overall understanding of the clinical trial recruitment process in oncology remains limited.17 A better understanding of this process is fundamental before considering strategies or solutions attempting to facilitate improvements. We do not have a clear appreciation for the proportion of eligible patients that we should expect to consent for trial participation, or what degree of variation between trials or between treatment institutions is likely to exist. There are only a few detailed examples in the cancer literature that would allow us to generate comprehensive recruitment measures, and collectively, these reports suggest that 40% to 63% of all new patients are potentially eligible for clinical trials; 43% to 61% of the potentially eligible patients are eligible; and 29% to 51% of eligible patients enter into clinical trials. Overall recruitment fractions to summarize these metrics of the recruitment process range from 18% to 22%.18-20 Each aspect and measure of the recruitment process may be of value to investigators through the conduct of a trial. Centers may be interested to know that their rate of patient acceptance for a specific trial is substantially lower than at other centers, at least prompting a review of the local approach with patients. Principal investigators would likely be responsive to data indicating that accrual to their trial is low because a high proportion of potentially eligible patients are being excluded by a singularly strict exclusion criterion such as time since surgery, or baseline laboratory values. Previous publications have questioned the use of other overly restrictive exclusion criteria in oncology trials.16,21,22 In select situations, this may be appropriate, but generally, excessive restrictions have resulted in fewer patients available to enter ongoing clinical trials and have limited the generalizability of the results. Improving the collection and reporting of recruitment statistics has been suggested for phase III trials in other medical specialties, with the intent of better understanding the generalizability of the trial results.2,23,24 The fact that most patients are not included in clinical trials is not unique to oncology. Other disciplines share the habit of tending to include younger, fitter patients in their clinical trials and perhaps overestimation of the effect of treatment.24,25 It must be acknowledged that collecting these type of data has significant resource implications, at a time when the nonclinical costs of research are significant.26 But as the availability of electronic screening and data linkages that simplify the accounting processes of clinical trials increase, we need to consider what data will be important to better our understanding of clinical trials and the patients enrolled on them. If every new trial began to routinely collect this information, it would be years before our published reports consistently provided such data. Population-based registries, such as accessed by Malmstrom et al, may be more immediate sources of target population data.7 In the short term, these type of data would facilitate more timely trial recruitment by providing both centralized trial reports and individualized site reports that could be used to identify problematic recruitment issues. Given the high costs associated with conducting clinical trials, accelerating the pace of recruitment may justify the incremental costs of collecting this data. Authors' Disclosures of Potential Conflicts of Interest and author contributions The authors indicated no potential conflicts of interest. Author Contributions
REFERENCES 1. Sackett D, Haynes B, Guyatt G, et al: Clinical Epidemiology: A Basic Science For Clinical Medicine (ed2). Boston, MA, Little Brown and Co, 1991 2. Gross P, Mallory R, Helat A, et al: Reporting the recruitment process in clinical trials: Who are these patients and how did they get there? Ann Intern Med 137:10-16, 2002 3. Pocock S: Clinical Trials: A Practical Approach. New York, NY, John Wiley & Sons, 1983, pp 35-38 4. Begg C, Cho M, Eastwood S, et al: Improving the quality of reporting of randomized controlled trials: The CONSORT statement. JAMA 276:637-639, 1996 5. Altman DG, Schulz K, Moher D, et al: The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med 134:663-694, 2001 6. Ando N, Iizuka T, Ide H, et al: Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: A Japan Clinical Oncology Group Study—JCOG9204. J Clin Oncol 21:4592-4596, 2003 7. Malmstrom P, Homlberg L, Anderson H, et al: Breast conservation surgery, with and without radiotherapy, in women with lymph node-negative breast cancer: A randomised clinical trial in a population with access to public mammography screening. Eur J Cancer 39:1690-1697, 2003[CrossRef][Medline] 8. Smit EF, Jan P, van Meerbeeck P, et al: Three-arm randomized study of two cisplatin-based regimens and paclitaxel plus gemcitabine in advanced non-small-cell lung cancer: A phase III trial of the European Organization for Research and Treatment Of Cancer Lung Cancer Group—EORTC 08975. J Clin Oncol 21:3909-3917, 2003 9. Moore MJ, Hamm J, Dancey J, et al: Comparison of gemcitabine versus the matrix metalloproteinase inhibitor bay 12-9566 in patients with advanced or metastatic adenocarcinoma of the pancreas—Phase III trial of the National Cancer Institute Of Canada Clinical Trials Group. J Clin Oncol 21:3296-3302, 2003 10. Vogelzang NJ, Rusthoven JJ, Symanowski J, et al: Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelionma. J Clin Oncol 21:2629-2630, 2003 11. Parnes HL, Cirrincione C, Aisner J, et al: Phase III study of cyclophosphamide, doxorubicin and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer And Leukemia Group B 9140. J Clin Oncol 21:1819-1824, 2003 12. Fuchs CS, Moore MR, Harker G: Phase III comparison of two irinotecan dosing regimens second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807-814, 2003 13. Bessell EM, Burton A, Haynes AP, et al: A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin's lymphoma. Ann Oncol 14:258-267, 2003 14. Reck M, vanPawel J, Macha HN, et al: Radomized phase III trial of paclitaxel, etoposide, and carboplatin versus carboplatin, etoposide, and vincristin patients with small-cell lung cancer. J Natl Cancer Inst 95:1118-1127, 2003 15. Rovers MM, Zielhuis GA, Bennett K, et al: Generalisability of clinical trials in otitis media with effusion. Int J Pediatr Otorhinolaryngol 60:29-40, 2001[CrossRef][Medline] 16. Begg CB, Engstrom P: Eligibility and extrapolation in cancer clinical trials. J Clin Oncol 5:962-968, 1987 17. Wright J, Fairclough L, Manzo J, et al: The metrics of clinical trials. J Clin Oncol 23:1589-1590, 2005 18. Hunter CP, Frelick RW, Feldman AR, et al: Selection factors in clinical trials: Results from the Community Clinical Oncology physician's patient log. Cancer Treat Rep 71:559-565, 1987[Medline] 19. Klabunde CN, Springer BC, Butler B, et al: Factors influencing enrolment in clinical trials for cancer treatment. South Med J 92:1189-1193, 1999[CrossRef][Medline] 20. Lara PN, Higdon R, Lim N, et al: Prospective evaluation of cancer clinical trial accrual patterns: Identifying potential barriers to enrolment. J Clin Oncol 19:1728-1733, 2001 21. Cassileth BR: Clinical trials: Time for action. J Clin Oncol 21:765-766, 2003 22. George S: Reducing patient eligibility criteria in cancer clinical trials. J Clin Oncol 14:1364-1370, 1996 23. Charlson ME, Horwitz RI: Applying results of randomised trials to clinical practice: Impact of losses before randomisation. BMJ (Clin Res Ed) 289:1281-1284, 1984 24. Moore DAJ, Goodall RL, Ives NJ, et al: How generalizable are the results of large randomized controlled trials of antiretroviral therapy? HIV Med 1:149-154, 2000[CrossRef][Medline] 25. Bjorn M, Brendstrup C, Karlsen S, et al: Consecutive screening and enrolment in clinical trials: The way to representative patient samples? J Card Fail 4:225-230, 1998[CrossRef][Medline] 26. Emanuel E, Schnipper L, Kamin D, et al: The non-treatment costs of conducting clinical research. J Clin Oncol 21:4145-4150, 2003
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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