Decreasing incidence of upper age restriction enrollment criteria among cancer clinical trials

Abstract

Background:

Age disparities among cancer clinical trial participants are pervasive and worsening over time. Identification of factors associated with age disparities is critical to improve enrollment of older patients on trials. The incidence and impact of trial eligibility criteria that exclude patients on the basis of age remains opaque.

Methods:

ClinicalTrials.gov was queried for completed oncologic randomized controlled trials (RCTs). Phase 3 RCTs assessing a therapeutic intervention among adult cancer patients were included. Trial eligibility criteria were assessed using the ClinicalTrials.gov website as well as trial publications and protocol documentation.

Results:

Seven hundred and forty-two trials met inclusion criteria, with a total combined enrollment of 449,720 patients. Upper age restriction enrollment criteria were identified for 10.1% of RCTs; the median age cutoff for restricted trials was 72 years (interquartile range 70–80 years). Linear regression modeling revealed decreasing incidence of age restriction criteria over time, at a rate of −1.1% annually (p = .03); trials initiating enrollment in 2002–2005, for example, had a 16.1% rate of age-restrictive eligibility criteria, compared with 7.6% for trials initiating enrollment in 2010–2014.

Conclusion:

Use of eligibility criteria that explicitly exclude patients on the basis of age appears to be decreasing with time. Future efforts should aim to better characterize the relationship between eligibility criteria (such as those that exclude patients on the basis of specific organ function) and their association with age disparities among enrolled patients.

1. Introduction

Age disparities among cancer clinical trial participants have long been recognized as a substantial concern within oncologic research [1–3]. Under-representation of older patients among cancer trial participants has the potential to profoundly impact the generalizability of trial results, particularly given the rapidly-growing population of geriatric cancer patients [4]. Recent data, unfortunately, suggest that age disparities among trial participants may be widening over time [5]. Ongoing efforts to improve trial inclusiveness and older patient representation have focused on trial eligibility criteria [6,7]. Enrollment criteria that exclude patients on the basis of age, a practice long under scrutiny at the regulatory level, remain relatively under-studied [8]. Therefore, we sought to characterize the incidence and correlates of age-restrictive eligibility criteria among oncologic randomized controlled trials (RCTs), as well as changes in the utilization of such age restrictions over time.

2. Materials and Methods

A database query was performed through the ClinicalTrials.gov website in November 2017 to identify oncologic RCTs for adult patients. The following search terms were utilized for this query: Terms: “cancer”; Study Type: “All Studies”; Status: excluded “Not yet recruiting”; Phase: Phase 3; and Study Results: “With Results.” This initial search yielded 1239 trials, which were then screened for cancer-specific phase 3 randomized multi-arm trials addressing a therapeutic intervention (including supportive measures) among adult patients (Fig. 1). Trials were assessed for eligibility criteria using the ClinicalTrials.gov website page per trial, as well as the primary publication of trial primary endpoint results and the trial protocol document, if available. Eligibility criteria assessed included explicit criteria regarding patient age cutoffs as well as performance status. Both trial screening and trial parameter identification were performed independently by two individuals. Statistical analyses included Pearson’s Chi-squared tests for comparison of proportions as well as linear regression analysis for analysis of temporal changes in the frequency of trial age restriction eligibility criteria. All statistical tests were two-sided, with an a priori α = 0.05 for statistical significance; all analyses were performed using SPSS (Version 22.0; Armonk, NY). Institutional review board approval was not required as all data were publically available without any use of protected health information.

Fig. 1.

Flowchart of trial screening and inclusion. Included trials then subdivided by the presence or absence of an eligibility criteria related to patient age. Abbreviations: RCTs, randomized controlled trials.

3. Results

Seven hundred and forty-two trials met inclusion criteria as oncologic RCTs for adult patients (Fig. 1); these trials collectively enrolled a total of 449,720 patients. Fourteen trials (1.9%) specified a lower age restriction cutoff as part of enrollment criteria, and all 14 trials aimed to test oncologic interventions specifically in either an “elderly” or “older” population per trial language (Fig. 1). Of the remaining 728 studies, 75 (10.3%, or 10.1% of the full 742 trial pool) included an upper age restriction as part of eligibility criteria (Fig. 1). A trial was considered to have an upper age restriction eligibility criteria if an age cutoff of 99 years or younger was provided. Twenty-five additional trials were identified that exclusively omitted centenarians (patients 100 years or older); these trials generally used an age cutoff of 120 years (in 19/25 trials), and these studies were not considered to be age-restricted trials for the purposes of this analysis. For those 75 trials with upper age restriction, the median age cutoff among restricted trials was 72 years (interquartile range 70–80 years, full range 46–90 years).

To identify factors associated with age restriction eligibility criteria, we then compared the 75 trials with an upper age restriction to the 653 trials without age restriction (Fig. 1; Table 1). Use of upper age restriction enrollment criteria was more common among cooperative-group-sponsored trials versus non-cooperative-group-sponsored trials (14.4% vs 8.7%, p = .03; Table 1). In addition to age restriction criteria, trial enrollment criteria were examined for performance status (PS) restriction; trials were considered to restrict patient PS if patients were limited to those with Eastern Cooperative Oncology Group PS 0–1 or Karnofsky PS 80 or higher. There was no relationship between age restriction and PS restriction criteria, with comparable rates of age restriction criteria for PS-restricted (10.1%) and PS-unrestricted trials (10.4%, p = .89; Table 1). By disease site, age restriction criteria were most common among hematologic trials (18.9%), and least common among genitourinary trials (3.3%, p = .001; Table 1). Among nonhematologic trials, studies evaluating patients with non-metastatic cancers used age restriction criteria more often than those evaluating patients with metastatic disease (16.3% vs 4.7%, p = .001; Table 1). By treatment modality, no trials evaluating a primary radiotherapy question used age restriction enrollment criteria, in contrast to studies assessing a systemic therapy (9.6%) or supportive care measure (13.0%, p = .009; Table 1). Among systemic therapy trials, those evaluating a targeted therapy (such as a small molecular inhibitor or monoclonal antibody) were less likely to utilize age restriction criteria than those assessing cytotoxic chemotherapy (7.1% vs 14.5%, p = .006; Table 1). Lastly, use of age restriction eligibility criteria did not predict for subsequent trial success (where success is defined as meeting the primary endpoint), with comparable rates of age restriction between studies meeting the primary endpoint (11.0%) and studies that did not (9.7%, p = .59; Table 1).

Table 1.

Trial factors associated with upper age limit eligibility restriction criteria.

Trial factor		No. of age-restricted trials / total (%)	p-value*
Industry funding of trial	Yes	51/553 (9.2%)	p = .09
	No	24/175 (13.7%)
Cooperative-group-sponsored trial	Yes	29/202 (14.4%)	p = .03
	No	46/526 (8.7%)
Study design	Superiority	58/565 (10.3%)	p = .33
	Non-inferiority	10/71 (14.1%)
Nation(s) of study enrollment	Multinational	43/498 (8.6%)	p < .001
	Uninational - United States	14/160 (8.8%)
	Uninational - Other	18/61 (29.5%)
Performance status restriction criteriaa	Yes	28/277 (10.1%)	p = .89
	No	47/451 (10.4%)
Disease site	Hematologic	27/143 (18.9%)	p < .001
	Breast	18/110 (16.4%)
	Gastrointestinal	9/90 (10.0%)
	Genitourinary	3/90 (3.3%)
	Thoracic	7/101 (6.9%)
	Other	11/169 (6.5%)
Solid tumor trials	Metastatic	18/382 (4.7%)	p < .001
	Non-metastatic	22/135 (16.3%)
Modalityb	Systemic therapy	52/544 (9.6%)	p = .009
	Surgery	3/7 (42.9%)
	Radiotherapy	0/19 (0.0%)
	Supportive care	20/154 (13.0%)
Systemic therapy subgroupc	Cytotoxic	26/179 (14.5%)	p = .006
	Chemotherapy
	Targeted Therapy	26/365 (7.1%)
Trial successd	Yes	33/300 (11.0%)	p = .59
	No	28/290 (9.7%)

Abbreviations: No., number; %, percentage.

^*p-values reflect Pearson’s Chi-squared test p-values comparing trial factors for proportions of trials utilizing upper age limit eligibility criteria.

^aTrials divided into those that restricted patients by performance status and those that did not; performance status restriction was defined as either Eastern Cooperative Oncology Group performance status 0–1 or Karnofsky performance status 80 or higher.

^bTreatment modality reflects the primary modality being tested in the trial.

^cSystemic therapy trials subdivided into those testing targeted therapies (including monoclonal antibodies, small molecular inhibitors, and similar) and those testing cytotoxic chemotherapy.

^dTrial success based on earliest publication of trial primary endpoint results; trials were omitted from this analysis if no peer-reviewed publication of trial primary endpoint results was identified.

Examining the utilization of age-related enrollment criteria over time, trials with explicit upper age restrictions appear to be decreasing with time. Linear regression modeling demonstrated an estimated annual change of −1.1% in the rate of trials using age restriction enrollment criteria (95% confidence interval for estimated annual change: −2.0% to −0.1%; r = 0.60; p = .03). Trials that initiated enrollment in 2002–2005, for instance, had a 16.1% (26/161) rate of age restriction enrollment criteria; by 2010–2014, this rate had dropped to 7.6% (15/197).

4. Discussion

In this evaluation of a large database of oncologic RCTs, we observed 10.1% of trials that include an explicit upper age restriction as an enrollment criterion. To our knowledge, this represents the first report to provide a broad analysis of the incidence of and factors associated with upper age restrictive eligibility criteria. Importantly, the use of upper age restriction criteria in cancer RCTs appears to be falling over time. Despite this, recent work from our group has demonstrated that age-based disparities among cancer trial participants may be widening over time [5]. These observations collectively suggest that explicit age restrictions are may not be the primary drivers of current age disparities among trial participants. Rather, eligibility criteria that restrict patients based on organ function (particularly renal, hepatic, and cardiac function), history of prior malignancy, and other comorbidities may disproportionately affect trial eligibility for older patients [2,6,7]. Moreover, under-representation of older patients among trial participants is the end-result of a complex combination of barriers, of which trial eligibility criteria are only one part [7]. Ongoing efforts to better characterize the relationship between certain eligibility criteria (including organ function criteria as well as exclusion criteria on the basis of prior malignancy) and subsequent age disparities among enrolled patients are currently underway. Identification of specific eligibility criteria that correlate strongly with age disparities among enrollees may better inform future efforts to bridge the age gap between trial participants and the broader cancer patient population.

The disconnect between explicit age restriction criteria and subsequent age disparities among trial participants is further emphasized by examining the roles of cooperative group and industry sponsorship. In the present study, age exclusion criteria were found in the present study to be more common among cooperative-group-sponsored trials, and a trend was noted where such criteria were less common among industry-funded trials. This is noteworthy in light of recent data highlighting significantly greater age disparities for trial participant enrolled on industry-supported trials [5]. Despite fewer industry-sponsored trials excluding patients based on age alone, these trials demonstrated wider age disparities between study participants and the general cancer population by disease site. Notably, this analysis of age disparities included the small percentage of trials (1.9% in this study) that were tailored specifically to older patients, limiting the comparison between these two analyses. Together, these data add evidence that ongoing age disparities among trial participants are unlikely to be explained by explicit age restrictions alone.

Disproportionately higher rates of age exclusion criteria were observed among hematologic cancer trials. This echoes previous data suggesting age restrictive enrollment criteria among 29% of hematologic phase 3 clinical trials [9]. On the other hand, of 14 trials identified in the current study with lower age limit eligibility criteria, 9 (64%) were specific to patients with hematologic malignancies. Therefore, hematologic cancer trials have increased incidence of both upper and lower age restriction enrollment criteria, suggesting that such trials are tailored to specific age demographics. While the basis for this is unclear, it is possible that patient tolerance for hematologic malignancy treatments is more directly associated with age-dependent physiologic factors than that for solid tumor treatments. Though such a broad generalization likely oversimplifies the situation, a greater dependence on hematologic and physiologic reserve may be necessary in the treatment of hematologic cancers. This could explain, at least in part, the observed predilection for age restrictions among hematologic cancer trials [9]. However, age as a surrogate for physiologic status in the context of clinical trials is imprecise; rather, more refined enrollment criteria focusing on those precise physiologic factors of interest should be utilized instead [9,10].

This study is limited through use of a single clinical trials registry based in the United States (ClinicalTrials.gov). Trials accruing in nations outside the United States have markedly higher rates of age-restrictive enrollment criteria; approximately 30% of these non-US studies use explicit upper age restrictions, which parallels data suggesting similarly high rates of age restrictions among Chinese and other non-US trials [11]. Therefore, our data likely underestimate the global impact of age-restrictive enrollment criteria, which may exert a more substantial effect on age disparities among trial participants on trials not based in the United States. Additionally, the justifications for age-restrictive criteria were not examined in this analysis; the underlying rationale for age restrictions among these trials, therefore, is not known. Finally, we only examined enrollment criteria that explicitly excluded on the basis of age. Efforts within our group are underway now to better characterize criteria that exclude patients on the basis of organ function, past medical history, and other comorbidities, all with the goal of elucidating any potential association with these and trial age disparities

Collectively, use of age restriction eligibility criteria among cancer clinical trials is decreasing over time. Despite this, age disparities among trial participants appear to be widening, and simply removing explicit age exclusion criteria will likely not suffice to ensure greater generalizability of trial findings. Future efforts must work to better ascertain the basis for such age disparities beyond criteria that explicitly restrict participation based on age.