Key Words

Clinical trials participation, barriers, insurance, Medicare, state laws. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Researchers from Yale University School of Medicine looked at enrollment in cancer clinical trials before and after changes to medical reimbursement policies that were intended to remove some of the economic barriers to clinical trial participation. In two separate reports, the researchers conclude that the removal of these barriers, by itself, is not enough to improve enrollment.

Source

Study 1: Journal of the National Cancer Institute, July 21, 2004 (see journal abstract)

Study 2: Archives of Internal Medicine, July 11, 2005 (see journal abstract)

Background

Only about three percent of adult cancer patients participate in clinical research studies. Researchers have identified a number of barriers to clinical trial enrollment, including lack of awareness, reluctance by physicians to refer patients to clinical trials, distrust of clinical researchers, inconvenience of participating, and concerns about the costs of participating in clinical studies.

Enrollment of older persons into clinical studies seems to be especially difficult. While about two-thirds of all cancer patients are over the age of 65, this age group represents less than one-third of clinical trial enrollees. The general barriers to clinical trial enrollment may be heightened for older patients, who may be seen by their doctors as too frail to withstand experimental treatments, may be less able to travel for treatment, and may have lower incomes.

Among the cost concerns is the fact that some insurance providers do not pay for a patient’s “routine care costs” if he or she enrolls in a clinical trial. Routine care costs include such things as doctor visits, hospital stays, clinical laboratory tests, x-rays, etc., that patients would receive whether or not they were participating in a clinical trial.

The two studies described here, which share some of the same authors, were designed to see if more people enrolled in clinical trials after changes to policies requiring their insurance providers to cover such costs during a trial. (For related information, see States That Require Health Plans to Cover Patient Care Costs in Clinical Trials and Medicare Coverage of Clinical Trials.)

The study teams for both reports were led by Cary P. Gross, M.D., of Yale University School of Medicine in New Haven, Conn.

Study 1

In the first study, published in the Journal of the National Cancer Institute (JNCI) in July 2004, researchers examined the potential impact on clinical trial enrollment of policies enacted in four states during 1999 requiring medical insurers to cover the routine care costs associated with participation in clinical trials. That year, the states of Illinois, Louisiana, and Virginia enacted laws requiring such coverage, while New Jersey health care plans voluntarily agreed to provide such coverage.

The researchers examined enrollment in phase II and phase III cancer clinical trials several years before and after these policies were enacted – specifically, between 1996 and 2001. They limited their study to privately insured patients under the age of 65 and compared trial enrollment figures in the four states to 35 states that had no mandated coverage by the end of 2001. (Residents of 11 other states that had enacted laws or agreements providing coverage in years other than 1999 were excluded from this study.)

The study was limited to participants in National Cancer Institute (NCI) sponsored cooperative group trials for breast, lung, colorectal, and prostate cancer, the four most common causes of cancer mortality for the study period.

Enrollment rates for coverage states versus noncoverage states were analyzed in three parts. (The enrollment rate was defined as the percentage of cancer patients in each group of states who enrolled in clinical trials, as determined by dividing the number of clinical trial participants by the estimated number of newly diagnosed cancer patients.)

First, the researchers looked at enrollment rates in 1996 to set a baseline. Second, they compared enrollment rate trends over time by examining the two years prior to enactment of coverage mandates (1997-98) and the two years following the mandates (2000-01). Third, the researchers explored how the enrollment rates changed following the enactment of mandates in 1999.

Study 1 Results

The 1996 baseline assessment revealed that clinical trial enrollment rates in the four states that would be covered in 1999 were already higher than in those states without coverage and in the states excluded from the analysis. These findings were statistically significant. However, during that year, enrollment in cancer clinical trials was growing at a similar rate in all three groups.

When researchers looked at the whole study period of 1996 to 2001, there were statistically significant increases in enrollment rates in both the coverage states (24.9 percent increase in enrollment per year) and the noncoverage states (28.8 percent increase per year). The rate of increase in the noncoverage states was significantly higher than in the coverage states.

During the pre-mandate period, clinical trial enrollment increased by 22.1 percent per year in the coverage states and 24.9 percent per year in the noncoverage states. After the mandates were enacted in 1999, the annual enrollment rate increase in the coverage states was 16.6 percent. In the noncoverage states, the enrollment rate increase was 22.1 percent. In other words, enrollments rates in the coverage states did not rise any more quickly in the states that had enacted mandates than in the non-mandate states.

When examined by trial phase, states with mandated coverage experienced statistically significant increases in enrollment of 21.7 percent per year in phase II trials following the mandates, while enrollment rates in noncoverage states for phase II trials decreased by 15.6 percent annually. Conversely, noncoverage states experienced a statistically significantly greater increase in the rate of enrollment in phase III trials (25.5 percent versus 16.2 percent).

The researchers offered some explanations for why state mandates seemed to boost enrollment in phase II trials but not phase III trials. “We had hypothesized that coverage policies are more likely to have an impact on phase II enrollment than phase III enrollment due to the more ‘experimental’ nature of these studies and the associated difficulties with obtaining reimbursement,” the researchers wrote.

Additionally, they suggested that those states that enacted reimbursement policies likely provided a more favorable climate for clinical research, with perhaps a greater density of research institutions and stronger advocacy and support groups. Thus, those states may have had greater public support and awareness of cancer research, with less room for improvements in trial enrollment during the study period.

Study 2

In the second study, published in the July 11, 2005, issue of the Archives of Internal Medicine, researchers examined potential changes in enrollment rates for persons aged 65 or older resulting from changes in the Medicare rules regarding reimbursement of costs associated with clinical trials. In 2000, the federal government changed the Medicare rules to authorize payment of routine care costs for beneficiaries participating in clinical trials.

The researchers examined enrollment rates from January 1996 to June 2003 for persons aged 65 or older in NCI-sponsored cooperative group trials for breast, lung, colorectal, and prostate cancer, the four most common causes of cancer mortality for the study period.

The analysis was conducted in two parts. First, the researchers looked at enrollment of older patients into a specific group of 23 trials that were recruiting both before and after the Medicare policy change. Second, they analyzed enrollment figures for all participants in cooperative group trials during the 10 quarter periods before 2000 (June 1997-December 1999) and the 10 quarter periods after 2000 (January 2001 to June 2003).

Study 2 Results

Enrollment of older patients into cancer clinical trials was either stable or decreased following the Medicare policy change. Representation of older patients in lung and breast cancer trials did not change, while statistically significant decreases occurred in elderly patients enrolling in colorectal cancer trials (45.7 percent of enrolled patients before versus 40.1 percent after) and prostate cancer trials (73.3 percent versus 67.0 percent).

When enrollment in each of the 23 specific trials was analyzed independently, only two trials had statistically significant changes in enrollment of older patients following the policy change. In one breast cancer trial, the proportion of elderly patients decreased from 29.7 percent to 20.9 percent, while in one prostate cancer trial, enrollment of elderly patients increased from 68.0 percent to 85.4 percent. Both findings were statistically significant.

When analyzed by phase, overall participation of elderly patients in phase III trials did not change significantly for any of the four cancer types, while a nonsignificant trend toward increased enrollment of elderly patients in phase I and phase II trials was observed following the Medicare policy change (40.9 percent to 49.3 percent).

As in the study on state mandates (Study 1), the researchers theorized that the Medicare policy change might have affected participation in early phase trials more greatly because these studies tend to be more experimental in nature and therefore less likely to have been covered previously.

Limitations

The selection of which cancer clinical trials to examine in these studies is an important limitation to consider. The studies looked exclusively at enrollment into NCI-sponsored cooperative group trials conducted for the four selected cancer types.

The researchers note that state mandates and Medicare reimbursement may affect enrollment into trials for other types of cancer differently. Additionally “we don’t know if these results reflect trends in enrollment into trials conducted by the NCI-designated cancer centers or by industry,” said Ted Trimble, M.D., of the National Cancer Institute’s Cancer Therapy Evaluation Program.

Researchers with the two studies also noted that the follow-up time in these studies was short, and that a longer interval may need to be examined before the effects of mandates and Medicare reimbursement on clinical trial enrollment become apparent.

Comments

Taken together, these studies indicate that insurance coverage barriers are only one factor that limits enrollment in clinical trials. Removing those barriers will not, by itself, improve participation in cancer clinical trials.

“State mandates and Medicare reimbursement do not appear to be meaningful drivers of patient accrual,” said lead researcher Cary P. Gross, M.D., of Yale University School of Medicine.. “Assurance that payers such as third-party insurers and Medicare will cover routine care costs associated with clinical trials is an essential element in improving enrollment rates, but that assurance alone is not a sufficient mechanism for increasing enrollment.”

“There are numerous barriers to clinical trial enrollment,” said Trimble. “In retrospect, the lack of coverage by Medicare and other third-party payers wasn’t as big of a barrier as we thought.”

Although the results of these studies are mixed, they do provide important pieces to the puzzle of improving clinical trials enrollment. “The apparent increase in access to early phase studies observed in the JNCI study does show that state legislation can help, just not as much as we had hoped,” said Trimble.

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