Transparency Around Disapproval Reasons of Early-Phase Trial Proposals Submitted to the National Cancer Institute (NCI)
Year of Publication
Massett, Holly A.; Gravell, Amy; Waters, Brittany; Mishkin, Grace; Denicoff, Andrea
American Society of Clinical Oncology (ASCO)
Background: NCI’s ETCTN accepts Letters of Intent (LOI) for a new clinical trial either from a response to a solicitation for studies, or via unsolicited LOIs, where investigators independently propose novel studies. While the LOI approval rate for the first two years of the ETCTN was 100% for solicited LOI’s, it was only 36% for unsolicited LOIs. Therefore, we analyzed all ETCTN LOI disapproval letters (DL) for unsolicited LOIs to identify the major reasons for disapproval. Methods: A content analysis was conducted on DLs issued between March 2014 and March 2016 (N = 50). Two coders independently scored disapproval reasons per letter using a code sheet with 22 categories identified from a sample of DLs (Intercoder Reliability = 97%). Results: All DLs were issued for unsolicited LOIs (44% = Ph 1; 26% = Ph 1/2; 30% = Ph 2); 271 reasons were identified across the 50 DLs (mean = 5.4/DL). High-level categories included concerns with study design, scientific rationale, feasibility, modality and administrative reasons. The top disapproval reasons were: Insufficient preclinical animal model data (54% of DLs); weak rationale/background (52%); inadequate information for biomarker correlative studies (46%); dose/scheduling plan absent or weak (36%); clinical data not adequately advanced (34%); and, patient population not described/inconsistent with treatment (34%). Top reasons for Phase 1 and 1/2 LOIs resembled the total but Phase 2 LOIs deviated slightly, with ‘weak objective/endpoint’ and ‘biomarker correlative studies’ as top DL reasons. Other common reasons were problems with combination study agents, company/drug collaboration, and competing trials. Conclusions: The reasons for LOI disapproval can be categorized and quantified. To increase transparency in the NCI ETCTN LOI review process, disapproval reasons for each DL are now collected on a standardized coding sheet, and will be reported quarterly to ETCTN PIs. NCI will also meet with all Grant PIs in Spring, 2017 to jointly discuss concerns and explore quality improvement solutions regarding the LOI submission process. The outcome of this meeting will be reported at ASCO as part of our findings.