ARTICLE

Cancer Trial Enrollment After State-Mandated Reimbursement

C. P. Gross, V. Murthy, Y. Li, A. D. Kaluzny, H. M. Krumholz

Affiliations of authors: Sections of General Internal Medicine (CPG, VM) and Cardiovascular Medicine (HMK), Department of Medicine, Robert Wood Johnson Clinical Scholars Program (CPG, HMK), Yale-New Haven Hospital Center for Outcomes Research and Evaluation (CPG, HMK), Section of Health Policy and Administration (HMK), Division of Biostatistics (YL), Department of Epidemiology and Public Health, (HMK) Yale University School of Medicine, New Haven, CT; Department of Health Policy and Administration, University of North Carolina School of Public Health, Chapel Hill, NC (ADK)

Correspondence to: Cary P. Gross, MD, Yale University School of Medicine, Primary Care Center, 333 Cedar St., P.O. Box 208025, New Haven, CT 06520 (e-mail: cary.gross{at}yale.edu)


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 
Background: Recruitment of patients into cancer research studies is exceedingly difficult, particularly for early phase trials. Payer reimbursement policies are a frequently cited barrier. We examined whether state policies that ensure coverage of routine medical care costs for cancer trial participants are associated with an increase in clinical trial enrollment. Methods: We used logistic Poisson regressions to analyze enrollment in National Cancer Institute phase II and phase III Clinical Trials Cooperative Group trials and compared changes in trial enrollment rates between 1996 and 2001 of privately insured cancer patients who resided in the four states that enacted coverage policies in 1999 with enrollment rates in states without such policies. All statistical tests were two-sided. Results: Trial enrollment rates increased in the coverage and noncoverage states by 24.9% (95% confidence interval [CI] = 22.8% to 27.0%) and 28.8% (95% CI = 27.7% to 29.8%) per year, respectively, from 1996 through 2001. After implementation of the coverage policies in 1999 in four states, there was a 21.7% (95% CI = 3.8% to 42.6%) annual increase in phase II trial enrollment in coverage states, compared with a 15.6% (95% CI = 8.8% to 21.8%) annual decrease in noncoverage states (P<.001). After accounting for secular trend, cancer type, and race in multivariable analyses, the odds ratio (OR) for a phase II trial participant residing in a coverage versus a noncoverage state after 1999 was 1.59 per year (95% CI = 1.22 to 2.07; P = .001). In a multivariable analysis of phase III trial participation, there was a decrease in the odds of residing in a coverage state after 1999 (OR = 0.90, 95% CI = 0.84 to 0.98; P = .011). Conclusion: State coverage policies were associated with a statistically significant increase in phase II cancer trial participation and did not increase phase III cancer trial enrollment.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 
Recent advances in genetics and immunology, coupled with a better understanding of cancer biology, have yielded important new anticancer agents with tremendous therapeutic potential (1). However, clinical trial recruitment has often been cited as the rate-limiting step in the translation of this new knowledge to the bedside, with fewer than 3% of adult cancer patients currently participating in clinical research studies (14).

Numerous factors can hinder the enrollment of eligible patients in trials. Many patients may not be aware of trials for which they may be eligible. Patients may have specific treatment preferences, based on knowledge of side effects, expense, risk, or inconvenience, that would hamper enrollment efforts. Important sociocultural factors, particularly the legacy of the Tuskegee syphilis study, have led many people to be wary of the motivations of researchers in general (5). Physician factors also play an important role because lack of awareness of available protocols or their specific eligibility criteria preclude many from participating in research trials (6,7). Some physicians may be reluctant to refer patients for trial enrollment because they do not want to forgo management decisions or lose contact with their patients altogether (8,9).

In addition to these important patient and physician factors, payer reimbursement policies are a frequently cited barrier to recruiting patients into clinical studies (7,10). Many private insurers do not routinely cover patient care costs for "investigational treatments," particularly for patients seeking to participate in phase I or phase II trials (1114). As many as 60% of patients who decline participation in clinical trials cite concerns about lack of reimbursement for their routine cancer treatment costs as one of the primary reasons for their lack of participation (15). The 1997 Board of Scientific Advisors Report of the National Cancer Institute Clinical Trials Program Review Group stated, "Lack of third-party reimbursement for clinical trials may be one of the most critical barriers to patient participation."

Policy makers, in an attempt to improve access of patients to cancer trials, have developed legislative remedies to address these reimbursement concerns. Between 1994 and 2001, 15 states either passed legislative mandates or entered into mutual agreements with large health plans to ensure reimbursement of routine medical costs for clinical trial participants (16,17). Critics of state mandates argue that they are arbitrary responses to clinical issues identified via a political process rather than the consequence of a measured discussion of medical necessity (1820). Payers complain that coverage mandates increase insurance premiums and thus may cause people to lose health insurance (2123), an ironic outcome given their stated aim of providing coverage. The impact on patient care is also uncertain because legislation does not usually include a mechanism to evaluate the effect of the mandated coverage.

Given the considerable effort and resources that are being invested toward enhancing recruitment to cancer research studies, it is essential to determine which strategies are effective. Accordingly, we sought to determine whether state policies that ensure coverage of routine medical care costs for privately insured cancer research participants are effective. In this study, we assessed whether enactment of state coverage mandates or similar "cooperative agreements" were associated with a subsequent increase in cancer trial enrollment. We repeated the analysis after stratifying by trial phase because we hypothesized that phase II enrollment might be particularly affected by reimbursement policies due to the increased likelihood that the trials might be perceived as investigational treatment.


    METHODS AND SUBJECTS
 Top
 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 
Study Overview

We performed a retrospective longitudinal analysis in which we examined trends in participation in National Cancer Institute (NCI)–sponsored phase II and III Clinical Trial Cooperative Group (CTCG) trials from 1996 through 2001. We restricted our analysis to patients with lung, breast, colorectal, and prostate cancer, the four most common causes of cancer death during the study period (24). We compared the trend in trial participation rates in the four states that enacted reimbursement policies in 1999 with the trend in enrollment in states without such policies. Because we hypothesized that there was an increase in trial enrollment nationally during the study period, we specifically explored whether the enactment of state reimbursement policies was associated with an increase in enrollment greater than what was observed in states without reimbursement policies.

State Coverage Policies

We obtained information about state coverage mandates enacted through 2001 from an American Association of Health Plans report (17). To ensure an adequate amount of time to evaluate trends before and after the enactment of these policies, we decided a priori to assess the impact of reimbursement mandates and agreements enacted in 1999. Illinois, Louisiana, and Virginia enacted legislation mandating coverage for clinical trial patient care costs in 1999. In the same year, members of the New Jersey Association of Health Plans, which includes the state's 10 largest health insurers and covers approximately 4.8 million beneficiaries, agreed to cover routine medical care costs of members enrolled in cancer clinical trials (16). We confirmed the specific details of each state mandate's requirements, evaluation, and enforcement protocol by contacting personnel from each state's Department of Insurance or its equivalent. New Jersey's cooperative agreement, which effectively preempted passage of a mandate in that state, is more comprehensive than the other state mandates in terms of the number of patients affected and the types of research included.

Patients were assigned to states based on their home ZIP code. We excluded patients who lived in one of the 11 states that had enacted policies in other years (either before or after 1999). Patients who lived in one of the other 35 states that had not enacted any policies by the end of 2001 served as the control group.

Cancer Research Participation

Enrollment data for NCI-sponsored therapeutic trials were obtained from the NCI's Clinical Data Update System (CDUS) (25). Investigators participating in all NCI CTCG trials are required to report patient enrollment information to the CDUS (25). American Cancer Society data were used to estimate the total number of cancer cases diagnosed annually in each group of states (2631).

Study Sample

We restricted our analysis to NCI-sponsored phase II and III CTCG trials because many state reimbursement policies focused exclusively on these types of studies. We also limited our primary analysis to patients who were younger than 65 years because a new Medicare policy was enacted during the study period that explicitly authorized payment for Medicare-covered services for clinical trials (32). Although we focused our analysis on privately insured patients because coverage mandates could be expected to affect this group in particular, we also repeated our analysis, including all patients, regardless of insurance status.

Statistical Analysis

Our analysis was conducted in three parts. We first compared the enrollment rates in each group of states during 1996. We defined the trial enrollment rate for each group of states as the number of trial participants, inclusive of all age groups and payer categories, in that group divided by the estimated number of newly diagnosed cancer patients in that state group. Using the Wald test, we compared these baseline enrollment rates of the noncoverage and excluded states (states that had enacted policies in years other than 1999) with the coverage states separately. We used a Poisson regression to determine whether there was an increase in overall enrollment rate (for all states combined) during the study period.

In the second part of the analysis, we assessed enrollment rate trends across time in coverage versus noncoverage states. For each group of states, we estimated the annual change in trial enrollment by using a Poisson model with the number of trial participants as the outcome, year as the independent variable, and log of the annual number of incident cancer cases as an offset. To compare enrollment trends between coverage and noncoverage states, we expanded the Poisson model to include an indicator variable for coverage state group and an interaction term between year and the coverage state group indicator variable. We compared the trend between the coverage and noncoverage state groups by the Wald test of the null hypothesis for this interaction term. We repeated this analysis using only the premandate (1996–1999) and postmandate (1999–2001) periods and also after stratifying by phase of trial.

In the third part of our analysis, we explored whether there was a more rapid increase in enrollment in the coverage states than in noncoverage states after the mandates were enacted in 1999. We constructed a logistic regression model with residence in a coverage state as the outcome variable and calendar year as the independent variable. We allowed for a change in the slope with time in 1999, the year of mandate passage, by incorporating a linear spline in 1999. Other covariates included year (1996–2001), cancer type, race, and phase of trial. Because our a priori hypothesis was that mandates might have a greater impact on phase II trial recruitment than phase III trial recruitment, we assessed for such an interaction and then repeated the Poisson regression after stratifying by phase of study. All P values were two-tailed.


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 
A total of 72 709 patients with breast, colorectal, lung, or prostate cancer enrolled in NCI phase II or III collaborative group trials between 1996 and 2001 in the United States. After excluding patients who had missing ZIP codes (8788), we assessed trial enrollment rate in coverage and noncoverage states as well as the states that were excluded from our analysis. Considering all 50 states, there was a statistically significant increase in trial enrollment rate between 1996 (0.99%) and 2001 (2.16%; Poisson P value for change in enrollment, P<.001).

We first investigated whether there were baseline differences in trial enrollment rates among the state groups (Table 1). In 1996, the trial enrollment rates were statistically significantly higher in coverage states (1.23%) than in noncoverage states (0.96%; P<.001) or in states that were excluded from our analysis (1.07%; P<.0001; Fig. 1). Despite these differences in baseline enrollment rate, there was no statistically significant difference in the trend in enrollment across the three groups (Poisson regression, P = 0.62; Fig. 1).


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Table 1. Clinical trial reimbursement policies by state

 


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Fig. 1. Trial enrollment rates by state group, 1996–2001. Percentage of incident cancer patients enrolled in NCI phase II and phase III cooperative group trials according to state group. The solid line represents patients living in states that enacted reimbursement mandates (Coverage), the hatched line represents patients living in states that did not enact reimbursement mandates (Noncoverage), and the dotted line represents other (Other) patients. The vertical line indicates the year in which state mandates were enacted to reimburse patients for trial enrollment costs.

 
We next set out to determine whether reimbursement mandates were associated with an increase in enrollment of privately insured patients. After excluding additional patients who lived in one of the 11 excluded states (11 525 patients) or who met other exclusion criteria (age ≥65 years [16 098 patients] or <20 years [19 patients], no private insurance [5731 patients], missing insurance data [5536]), the final study sample of privately insured patients consisted of 25 012 patients (Table 2). The majority of the patients were white (88.8%); African American participants made up 7.3% and Hispanics made up 1.5% of study participants. Breast cancer was by far the more common cancer type (68.4%), followed by colon (17.0%), lung (10.8%), and prostate (3.8%). There was a statistically significant increase in phase II and III trial enrollment among patients with private insurance during 1996–2001 in both coverage (Table 3: 24.9% increase per year, 95% CI = 22.8% to 27.0%) and noncoverage (Table 3: 28.8% increase per year, 95% CI = 27.7% to 29.8%) states. This rate of increase in the coverage states was statistically significantly higher than that in the noncoverage states (Poisson regression for difference between state groups, P<.001; Table 3). During the premandate period (1996–1999), trial enrollment increased by 22.1% (95% CI = 17.7% to 26.6%) per year in the coverage states and 24.9% (95% CI = 22.8% to 27.2%) per year in the noncoverage states (Poisson regression for difference, P = .26). After the reimbursement policies were enacted in 1999, the annual enrollment increases were 16.6% (95% CI = 11.5% to 21.8%) for the coverage states and 22.1% (95% CI = 19.6% to 24.7%) for the noncoverage states (Poisson regression for difference, P = .06).


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Table 2. Definition of the study sample*

 

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Table 3. Percent annual increase* in cancer trial enrollment according to category of state trial coverage policy

 
After stratifying by trial phase, we found that states with coverage policies experienced a greater increase in phase II enrollment than the noncoverage states. In the postmandate period (1999–2001), there was a 21.7% (95% CI = 3.8% to 42.6%) annual increase in enrollment in phase II trials in coverage states, compared with a 15.6% (95% CI = 8.8% to 21.8%) decrease in enrollment in noncoverage states (P<.001; Table 3). As demonstrated in Fig. 2, phase II enrollment in the four coverage states increased from 60 patients in 1999 to 95 in 2001. Conversely, there was a relative increase in phase III enrollment in noncoverage states in comparison to coverage states (25.5% versus 16.2%, respectively; P = .002; Table 3)



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Fig. 2. Cancer trial accrual of privately insured patients according to trial phase, 1996–2001. Annual number of phase II (lower panel) and phase III (upper panel) trial participants in states that enacted reimbursement mandates (diamonds and hatched line) and states that did not (squares and solid line). The vertical line indicates the year in which state mandates were enacted to reimburse patients for trial enrollment costs.

 
After adjusting for secular enrollment trends, cancer type, and ethnicity with multivariable analysis, coverage policies were still not associated with a statistically significant increase in trial enrollment of patients with private insurance (Table 4, Model A; P = .25). This finding was consistent when patients with all types of payers were included (Table 4, Model D; P = .77). In the multivariable model, there was a significant interaction between the trial phase and the impact of coverage policies (P<.001 for interaction terms when added to models A and D in Table 4). In subsequent stratified analyses, mandate enactment was associated with a statistically significant increase in enrollment in phase II trials, even after accounting for secular trend. Among privately insured trial participants, the odds ratio (OR) for participants residing in a coverage state (compared with those living in noncoverage states) was 1.59 per year (Table 4, Model C; P = .001) after enactment of the coverage policies. The results were similar when all participants were included in the model (Model F: OR = 1.68 per year; P<.001).


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Table 4. Multivariable models

 
Although phase II participation increased more rapidly in coverage states than in noncoverage states after policy enactment, the opposite was true for phase III studies. Among patients with private insurance, the rate of increase in trial participation was statistically significantly lower in coverage states after enactment of the coverage policies (Table 4, Model B; OR = 0.90; P = .011). There was a similar, although nonsignificant, trend among patients with all types of insurance (Table 4, Model E; OR = 0.95; P =.12).


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 
Our analysis suggests that statewide policies ensuring reimbursement for routine medical care costs were not associated with a substantial increase in overall clinical trial enrollment. However, we did find that enactment of coverage policies in four states in 1999 was associated with a statistically significant increase in phase II trial enrollment during 1999–2001 compared with that in noncoverage states. The differential impact of reimbursement policies was not unexpected because 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.

Although the absolute increase in phase II trial participation was relatively low (from about 60–70 per year in the premandate period to 95 in 2001 in the four coverage states), the true impact of coverage policies might have been far more substantial given that federally sponsored trials now represent a minority of clinical research (33,34). Furthermore, the mean sample size of phase II trials in our sample was 60 patients, which represents about 1/10 the sample size of the phase III trials. Hence, relatively small gains in phase II recruitment could yield substantive increases in the number of trials completed annually with little incremental cost (35,36).

Despite the importance of deriving evidence that can guide clinical decision-making for the full spectrum of cancer patients, we found that only 1%–2% of incident cancer patients are participating in NCI-sponsored group trials. This finding is consistent with earlier estimates (37). Although we did find a substantial increase in enrollment rate from 1%–2% during our study period, this rate still represents a fraction of the 10%–15% recruitment target recently set by a coalition of cancer research groups (37).

We found that trial participation rates were higher in coverage states than in noncoverage states in the baseline year (1996). The same factors that led to a higher enrollment rate in these states (such as density of research-intense institutions or advocacy and support groups) may have been associated with their legislators being more likely to enact reimbursement policies. These baseline differences may explain the paradoxically faster increase in phase III trial enrollment in noncoverage states after enactment of the coverage policies. Perhaps there was more "room for improvement" in the noncoverage states, and because overall NCI funding increased during the time period, the effect on these states was greater, even though they lacked coverage policies.

Why was the impact of these state policies mandating coverage on phase III enrollment so low? Reimbursement represents only a single barrier to enrollment; patient, physician, and health system factors can also impede participation in research for cancer patients (79, 3841). Many patients may have been unaware, unwilling, or ineligible to participate in research, regardless of their payer coverage policies. Community physicians may be unaware of potentially appropriate studies or reimbursement policies and, even if knowledgeable, may lack the infrastructure and resources needed to successfully engage in clinical research (42).

There are insufficient data to determine whether lack of enforcement impaired the impact of the mandates and hence the effect on phase III trial enrollment. In addition, it is possible that the mandates simply made legitimate those reimbursements that were already being secured by physicians for routine clinical trial care costs. Prior evidence has suggested that physicians have sometimes misrepresented information to insurance companies to obtain reimbursement for their patients’ treatment (43,44).

The voluntary nature of the New Jersey cooperative agreement (as opposed to a state legislative measure) has important implications. Because of Employment Retirement Income Security Act (ERISA) provisions at the federal level, the legislative mandates in Illinois, Louisiana, and Virginia did not apply to patients covered through self-insured entities. State mandates that apply only to group plans will cover less than one-third of a state's population (21). In contrast, New Jersey's voluntary agreement included a broad range of payers, including some large self-insured ERISA plans as well as the state Medicaid program (45). The result was that a greater percentage of cancer patients was covered by the New Jersey mandate than would have been had this state enacted a legislative measure. This broader coverage of the New Jersey approach raises the important question of whether it is more encompassing and hence more effective to work out a voluntary agreement versus dictating coverage via legislation. Efforts to increase diversity of trial participants may be hampered by coverage requirements that apply only to privately insured patients.

Because our study did not include clinical research sponsored by industry or by NCI-funded trials not conducted through CTCGs, we were unable to assess whether patient accrual to these trials was affected by state mandates. It is also possible, given the limited follow-up time, that a longer interval may be required to determine the effect of the mandates on clinical trial enrollment. Finally, the use of incident cancer cases as the denominator for our definition of enrollment rate likely yielded an overestimate of the proportion of cancer patients enrolled in CTCG trials. We selected incidence because annual estimates of state cancer incidence are more readily available and rely on fewer assumptions than prevalence estimates. Because our analysis focused on trends rather than single cross-sectional estimates, it is unlikely that the use of annual incidence data biased our results. Further, we limited our multivariable analysis to trial participants to avoid this potential bias.

The clinical trial coverage mandates have developed in the context of other efforts to increase cancer research participation, including broadening community physician participation, increasing investment in research and informatics infrastructure, easing administrative and financial burdens on busy clinicians who are interested in participating, and broadening public education (46,47). The NCI recently announced a collaborative program with several pharmaceutical companies to increase recruitment rates to early phase clinical trials (48). Notably, several federal legislative initiatives that incorporate clinical trial coverage mandates have stalled in Congress (49). Policy makers should appreciate that mandates alone may inadequately address the barriers to high-quality healthcare. Our findings, which are consistent with those of a prior study showing the modest impact of state mammography mandates, strongly suggest that mandate legislation should include a follow-up evaluation component (50,51).

In summary, our analysis suggests that the state mandates and reimbursement agreements yielded mixed results. Phase II studies are critical for assessing the safety and efficacy of new agents, and our data suggest that state policies may have had a positive impact on recruitment into these trials. However, phase III enrollment was not increased by coverage mandates. It is likely that physician and patient knowledge, beliefs, and attitudes concerning trials, as well as logistical barriers, have a greater influence on patient participation than legislative mandates. Coverage policies may be a necessary but insufficient solution to adequate patient participation in cancer research. To generate a substantial increase in research participation, a multifactorial approach including enhanced community partnerships and public education will be needed.


    NOTES
 Top
 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 
Supported by a Cancer Prevention, Control, and Population Sciences Career Development Award (1K07CA-90402) and the Claude D. Pepper Older Americans Independence Center at Yale (P30AG21342).


    REFERENCES
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 Notes
 Abstract
 Introduction
 Methods and Subjects
 Results
 Discussion
 References
 

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Manuscript received November 7, 2003; revised May 10, 2004; accepted May 18, 2004.


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