Abstract
Clinical trial eligibility criteria can unfairly exclude patients or unnecessarily expose them to known risks if criteria are not concordant with drug safety. There are few data evaluating the extent to which acute leukemia eligibility criteria are justified. We analyzed criteria and drug safety data for front-line phase II and/or III acute leukemia trials with start dates 1/1/2010-12/31/2019 registered on clinicaltrials.gov. Multivariable analyses assessed concordance between criteria use and safety data (presence of criteria with a safety signal, or absence of criteria without a signal), and differences between criteria and safety-based limits. Of 250 eligible trials, concordant use of ejection fraction criteria was seen in 34.8%, corrected QT level (QTc) in 22.4%, bilirubin in 68.4%, aspartate transaminase/alanine aminotransferase (AST/ALT) in 58.8%, renal function in 68.4%, human immunodeficiency virus (HIV) in 54.8%, and hepatitis B and C in 42.0% and 41.2%. HIV and hepatitis B and C criteria use was concordant with safety data (adjusted Odds Ratios 2.04 [95%CI: 1.13, 3.66], 2.64 [95%CI: 1.38, 5.04], 2.27 [95%CI: 1.20, 4.32]) but organ function criteria were not (all P>0.05); phase III trials were not more concordant. Bilirubin criteria limits were the same as safety-based limits in 16.0% of trials, AST/ALT in 18.1%, and renal function in 13.9%; in 75.7%, 51.4%, and 56.5% of trials, criteria were more restrictive, respectively, by median differences of 0.2, 0.5, and 0.5 times the upper limits of normal. We found limited drug safety justifications for acute leukemia eligibility criteria. These data define criteria use and limits that can be rationally modified to increase patient inclusion and welfare.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1046-1052 |
| Number of pages | 7 |
| Journal | Haematologica |
| Volume | 109 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2024 |
Funding
In this analysis assessing the use, variability, and justification of acute leukemia clinical trial eligibility criteria, there was a substantial discordance between criteria and drug safety data. The use or absence of many criteria were related to anticipated risk, but large proportions were not. There was concordance between infectious disease criteria and risk, but this was not the case for organ function criteria, and the imposed criteria limits were similarly restrictive irrespective of anticipated risk. Despite the presumption that additional safety data would become available later in drug development, criteria use in phase III studies was not more concordant. When trial criteria use was concordant with safety data, the imposed criteria limits were generally more restrictive than drug safety data and were variable in their degree of restriction. Among these studies, phase III limits were somewhat more aligned with drug safety data than phase II, but their limits were no less variable. Together, these data identify specific criteria that sponsors and investigators should assess for inclusion, removal, and liberalization in order to improve representativeness and accrual, limit the implicit biases that can occur when criteria are not explicit, and improve patient safety.13 These data are consistent with solid tumor studies that demonstrate the presence of unjustified criteria and their potential impact on demographic inequities in participation.2,3 One such study used the Flatiron real-world database and found that if several enrollment criteria for non-small cell lung cancer immunotherapy trials were removed (e.g., neutrophil counts, CNS metastasis), the eligible population would be doubled and would only decrease the projected Hazard Ratio of overall survival by 0.05.3 A study in pancreatic cancer found that Black patients would have been less likely to participate owing to hepatitis and HIV status.2 The lack of justification for infectious disease exclusions in some of the trials in this analysis suggests this inequity may also be present in acute leukemia. To our knowledge, prior studies regarding acute leukemia enrollment criteria are aligned but distinct and do not address the question of use, variability, or justification across phase II and III studies. A trial published in 2017 enrolled patients with comorbid conditions, organ dysfunction, and poor performance status to show that a trial of low-intensity therapy was possible in this traditionally ineligible population.14This is important in that it shows trials, rather than just post-approval real-world analyses, are possible for most patient populations. At the same time, it did not assess heterogeneity in trial criteria and when criteria are justified or unjustified. A separate study from the FDA analyzed disparities in ineligibility of screened patients on 13 trials from 2016 to 2019 (N=3192), finding that 27% were ineligible. These data also showed that Black and Hispanic patients with AML were less likely to meet study eligibility requirements due to cardiac function and/or a lack of specific mutations.15 Notably, there was significant selection bias as the analysis was restricted to those who consented to participate, meaning that data on those who were known to be ineligible, and thus not approached, were not included. The present study adds significantly to this literature because it not only assesses criteria use but their variability and justification in drug safety. We found that there was wide variability within criteria with associated measures. Some criteria such as time since prior cancer diagnosis have limited justification, and others like bilirubin limits were not present despite known drug-related hepatotoxicity. We also saw that if a criterion was used, it was generally more restrictive than suggested by drug safety data. Criteria used were also similarly restrictive independent of if there were known drug-related risks. Taken together, these data identify criteria that should be specified and others that can be liberalized to promote a rational approach to maximizing the eligible pool of patients without compromising safety. The systematic approach used to catalog study drug safety profiles relative to enrollment criteria also minimizes the In summary, a substantial proportion of acute leukemia bias of prior studies, which did not account for the more clinical trial enrollment criteria do not appear justified limited knowledge of drug safety known during investiga-by drug safety. Both the FDA and the American Society of tional drug development. Though much of the previously Clinical Oncology have recognized this issue and adopted published literature focuses on criteria expansion, our positions requiring justification of criteria;16-18 these data study also identifies areas where known safety signals ex-identify where potentially unjustified criteria and limits ist, but explicit criteria are missing. This can put enrollees exist for acute leukemia and a rational approach to meet-at unnecessary risk, limit the identification of efficacious ing this goal while ensuring patient wellbeing. Judicious drugs, and may increase enrollment bias by leaving related minimization of criteria based on drug safety profiles and eligibility decisions to individual investigators. standardization are key to enhancing research represen-Applying these points to a study included in the analysis, tativeness, efficacy, and safety. we can see how trial eligibility may be modified in practice. This study tested the combination of nivolumab, cytara-Disclosures bine, and idarubicin in AML, and used exclusion criteria AH has received personal fees (advisory boards) from As- based on hepatic and renal lab values. The labels for the traZeneca and AbbVie. MRL reports receiving personal fees antineoplastic therapies used collectively identify hepatic (advisory boards) from Novartis and AbbVie. AAP has received and renal toxicity (among other side effects), justifying the institutional research funding from Kronos Bio, Pfizer, and trial\u2019s use of exclusion criteria related to liver and kidney Sumitumo, and personal fees from AbbVie (educational function. The study\u2019s hepatic and renal criteria limits were curriculum development) and Bristol Myers Squibb (advisory bilirubin \u2264 \uB402\u2801\uB802\u2300 ?ST/L T \u2264 \uB502\u2801\uB802\u2300 and creatinine \u2264 \uB402\u2801b\uB600oa tridm).e Ds JtDheeA has received research funding from Abbvie, ULN, and the conservative limits from drug labels were Novartis, Blueprint, and Glycomimetrics, and personal fees \u2264 \uB502\u2300 \u2264 \uB602\u2300 \u2264 \uB502\u2801\uB500 times the ULN, respecti \u0F00el ? . ?n -thisf rcoams eA, me g? en, Autolus, Blueprint, Gilead, Incyte, Jazz, Kite, pansion of renal and hepatic criteria by 0.5, 0.5, and 1.1 Novartis, Pfizer, Servier, and Takeda (consulting). GAA has times the ULN could be justified and potentially increase received personal fees (consulting) from Novartis. The other the eligible population while maintaining safety. A similar authors have no conflict of interests to disclose. process, applied systematically across new trials, would align eligibility with drug safety, expanding criteria limits Contributions in some trials, contracting limits in others, and making AH, CSL, GAA, IK and AAP are responsible for the study criteria explicit instead of inexact in the rest. concept. AH, EQ, TPW and GAA designed the methodolo- Limitations of this study include the potential for bias due gy. AH, EW and TPW collected the data. AH, EW, TPW and to safety data that were unpublished at the time of study GAA analyzed the data. AH, EW, TPW and GAA wrote the start, which we attempted to minimize through multi-modal manuscript. MRL, IK, AAP, DJDeA, CSL and GAA critically searches and use of trial protocols. This mirrors the in-reviewed the manuscript. All authors revised the manuscript vestigational drug safety data and eligibility requirements for publication. that enrolling physicians use during recruitment. While we focused on drug-safety profiles from individual drugs, we Acknowledgments could not capture safety justifications based on emerg-The authors would like to acknowledge the work of Dillon ing issues related to the overall intensity of a regimen, Clancy in assisting with data collection and preparing the where general eligibility restrictions for organ dysfunction figures. or comorbidities may be used. Nonetheless, there were a number of criteria not included where safety signal(s) Funding were identified which would not have been ameliorated. AH is supported by grants from the National Cancer Insti- The generalizability of the analysis is limited to clinical tute of the National Institutes of Health (K08 CA273043), the trials conducted under FDA regulation, which was done American Society of Clinical Oncology (Career Development to assess changes in criteria that could be made under Award), the Alliance in Clinical Trials for Oncology (Special a single regulatory standard. Cellular therapy trials were Projects Fund), and the Rieder Family Fellowship in Acute also excluded as the population eligible for cellular thera-Lymphoblastic Lymphoma. IK is supported by a grant from py treatment, even outside the research context, is much the American Cancer Society (CSDG-21-088-01-ET). The more restricted than the broader acute leukemia popula-sponsors had no role in gathering, analyzing, or interpreting tion. Other limitations include biases due to the necessary the data. The content of this publication does not necessarily aggregation of unstructured data into analytic variables, reflect the views or policies of the Department of Health which limited our ability to capture vague or inexact cri-and Human Services, nor does mention of trade names, teria, and required us to assume a uniform normal range commercial products, or organizations imply endorsement of laboratory values, and the moderate sample size, which by the US government. was limited by the availability of trials.
ASJC Scopus subject areas
- Hematology
