EDITORIAL

Barriers to Clinical Trial Enrollment: Are State Mandates the Solution?

Bruce E. Hillner

Correspondence to: Bruce E. Hillner, MD, Department of Internal Medicine and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298-0170 (e-mail: hillner{at}hsc.vcu.edu)

Everyone agrees that optimal medical care should be based upon a database of evidence derived from patients participating in comparative randomized clinical trials. Unfortunately, there are numerous barriers to building this database. The design, recruitment, and analysis of these trials are expensive and enmeshed with potential conflicts of interest (1,2). A variety of approaches has been suggested to enhance public participation in clinical research (3).

One easy-to-identify barrier is uncertainty about third-party insurers paying for care. Because no consensus in the United States about who is financially responsible for paying for these clinical trials has been reached, it is not surprising that private insurance plans have been reluctant to pay for care provided as part of a clinical trial (assuming they are aware of trial participation).

How great are the added costs to an insurer? Several recent studies have addressed the question. While none was based upon prospective data, their conclusion has been consistent: the incremental costs of care in government-sponsored phase III (randomized) trials compared with those of standard care are minimal (typically a <10% increase) (46). For pilot trials (phase I or II), there is much more uncertainty about the size of the added costs.

Even if the costs of randomized clinical trials are comparable to costs of standard care, the lack of insurance coverage has been a real or perceived barrier to enrollment. In response to the perception, cancer advocates have successfully lobbied for legislation in 17 states requiring health plans to pay for the costs of federally supported cancer clinical trials (7). These laws complement President Clinton's 2000 presidential decision for Medicare to begin paying for all routine care costs of participants in all (not just cancer) federally sponsored trials. The 1999 Commonwealth of Virginia statute is an example but covers only cancer trials (see Table 1). The only covered industry-supported trials are comparative ones supporting a Food and Drug Administration new-drug application.


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Table 1. Key components of the Virginia Statute on coverage for clinical trials in cancer*

 
What are the cost consequences of these mandates? At least in Virginia, the costs are minimal. In 2001, the impact was estimated at 0.3% of the overall average premium (8). This amount is the same as, or less than, other mandated coverage for cancer-related care (e.g., bone marrow transplants, common cancer screenings).

The bigger question to cancer providers and patients is "do these state statutes make a difference in enrollment?" In this issue of the Journal, Gross et al. (9) address this question by comparing trial enrollment rates between 1996 and 2001 of privately insured cancer patients who resided in four states that enacted coverage policies in 1999 with enrollment in states without such policies. Their key findings were that: 1) enrollment in phase III trials was increasing in all states independent of a legislative mandate, 2) the relative increase for phase III trials was no different in states with mandates, and 3) for phase II trials, states with mandates had a modest increase in enrollment compared with states without, where enrollment declined. I have concerns about the first two conclusions but not the third.

Gross et al. did not differentiate between cancer prevention and treatment trials in either their prior report on race-, sex-, and age-based disparities (10) or in this report on state mandates. The difference in trial intent accounts for key differences in size, design, cost, and ease of recruitment. During the 1996–2001 period, at least four large prevention trials were open: NSABP P-1 (closed September 1997), NSABP P-2 (opened July 1999), the Prostate Cancer Prevention Trial (closed December 1996), and the Prostate Cancer SELECT Trial (opened August 2001). Each of these has or will accrue thousands of subjects. It is possible that the majority of the growth in phase III enrollment was due to preferential enrollment in prevention studies. Whereas the observed annual increase (≥26% per year) in trial participation would be a blockbuster if these reflected mutual fund returns, this increase does not reflect current growth in the cancer knowledge base. A review of therapeutic clinical trial reports between 1989 and 2000 found an annual growth of 4.8% in breast cancer and 5.4% in colorectal cancer trials, with no evidence of a substantial increase in their sample size (11). With no disrespect to the cancer prevention community, the overwhelming purpose of state legislation was directed toward cancer treatment.

The observed divergent directions of enrollment in phase II trials supports the authors’ and my own expectation. Given the wide diversity of therapies and potential costs, insurance payment is likely to be a necessary but not dominant issue in enhancing enrollment. Solely focusing on the annual percent change obscures the effect in absolute enrollment. The absolute annual accrual in any year studied was modest (60–100 patients per year) in the four states (total population of approximately 31 million) and represent less than 0.2% of cancer patients.

By design, this report addresses only part of the clinical trial universe. The majority of pilot cancer trials are funded by the biotechnology industry and miscellaneous nonprofit organizations. Investigators in states without mandated coverage may have shifted their focus and recruitment efforts to commercial trials. Until there is a required registration of all initiated trials (12), an accurate estimate of total enrollment and the effect of mandates or other societal forces can only be speculated upon.

Concern about insurance may be diverting attention from more fundamental barriers to cancer trials. I am especially intrigued by one rarely discussed in other commentaries. Schwartz has written about the paradox of choice in contemporary society (13). He notes that being given more options does not necessarily make us happier or more satisfied in our decision making. I suggest that one of the under-recognized barriers to trial accrual and completion is having too many choices. To illustrate the point, Table 2 lists the number of National Cancer Institute (NCI)–supported trials available within 100 miles of Richmond for advanced-stage patients for each of the four most common cancers. If the target accrual per trial is 60 patients and 200 trials are open, then 12 000 patients are needed. Yet in these four cancers, about 1200 patients per year enrolled nationwide in NCI phase II trials between 1996 and 2001. More pilot trials may not increase the number of participants or their completion rate (14).


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Table 2. Number of open National Cancer Institute–sponsored clinical trials by design and cancer stage (within 100 miles of Richmond, VA)*

 
One simple reason is choice or information overload. Patients and providers cannot actively consider 40–70 different trials. No wonder the default approach is to not enter a trial. A minimally explored venue is how to use evolving information systems or other tools to target specific trials to specific patients based on specific biologic characteristics of the individual's cancer.

In summary, insurance mandates to require payment for cancer trials address one small hurdle in the long road to increasing enrollment in cancer clinical trials. The absolute financial burden on society is minimal. It is time to shift attention and resources to the numerous other barriers to expanding the foundation of evidence-based oncology care.

REFERENCES

1 Holmes DR Jr, Firth BG, James A, Winslow R, Hodgson PK, Gamble GL, et al. Conflict of interest. Am Heart J 2004;147:228–37.[ISI][Medline]

2 Bekelman JE, Li Y, Gross CP. Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA 2003;289:454–65.[Abstract/Free Full Text]

3 Sung NS, Crowley WF Jr, Genel M, Salber P, Sandy L, Sherwood LM, et al. Central challenges facing the national clinical research enterprise. JAMA 2003;289:1278–87.[Abstract/Free Full Text]

4 Goldman DP, Berry SH, McCabe MS, Kilgore ML, Potosky AL, Schoenbaum ML, et al. Incremental treatment costs in National Cancer Institute-sponsored clinical trials. JAMA 2003;289:2970–7.[Abstract/Free Full Text]

5 Wagner JL, Alberts SR, Sloan JA, Cha S, Killian J, O'Connell MJ, et al. Incremental costs of enrolling cancer patients in clinical trials: a population-based study [published erratum appears in J Natl Cancer Inst 2000;92:164–5]. J Natl Cancer Inst 1999;91:847–53.[Abstract/Free Full Text]

6 Fireman BH, Fehrenbacher L, Gruskin EP, Ray GT. Cost of care for patients in cancer clinical trials. J Natl Cancer Inst 2000;92:136–42.[Abstract/Free Full Text]

7 National Cancer Institute. States that require health plans to cover patient care costs in clinical trial. Available at: http://www.nci.nih.gov/clinicaltrials/developments/laws-about-clinical-trial-costs. [Last accessed: June 15, 2004.]

8 Reports to the General Assembly. The financial impact of mandated health insurance benefits and providers: 2001 reporting period; 2003. Available at: http://leg2.state.va.us/dls/_2d0j76p3fcdpg_.nsf/d035e5a60132441d85256b0a0063ec73/ea488a1e72fc452285256e1d00631d28?OpenDocument. [Last accessed: June 25, 2004.]

9 Gross CP, Murthy V, Kaluzny AD, Krumholz HM. Cancer trial enrollment after state-mandated reimbursement. J Natl Cancer Inst 2004;96:1063–9.[Abstract/Free Full Text]

10 Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical trials: race-, sex-, and age-based disparities. JAMA 2004;291:2720–6.[Abstract/Free Full Text]

11 Hillner BE. Trends in clinical trials reports in common cancers between 1989 and 2000. J Clin Oncol 2003;21:1850–8.[Abstract/Free Full Text]

12 Dickersin K, Rennie D. Registering clinical trials. JAMA 2003;290:516–23.[Abstract/Free Full Text]

13 Schwartz B. The paradox of choice: why more is less. 1st ed. New York (NY): Ecco; 2004.

14 Tannock IF. Collaborative clinical trials: quality or quantity? Int J Radiat Oncol Biol Phys 2001;49:339–43.[CrossRef][ISI][Medline]



             
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