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Patient Participation in Research Among Solid Organ Transplant Recipients in the United States

Schold, Jesse D.1,2,8; Buccini, Laura D.3; Goldfarb, David A.2,4; Flechner, Stuart M.4; Hsich, Eileen2,5; Mason, David6; Fung, John2,7; Stephany, Brian R.2,4; Krishnamurthi, Venkatesh4; Srinivas, Titte R.4

doi: 10.1097/TP.0b013e31821a20ee
Clinical and Translational Research

Background. In many healthcare contexts, evidence exists that patients who participate in research protocols (PRP) significantly differ from nonparticipants. These differences may affect the external validity of study findings, reflect access to care, and potentially explain sources of difference in patient outcomes. There is no comprehensive study evaluating PRP among transplant recipients.

Methods. We evaluated the national Scientific Registry of Transplant Recipients from 2000 to 2008 for liver, kidney, heart, lung, and simultaneous pancreas/kidney transplant recipients in the United States for which PRP for immunosuppressive medications is reported at follow-up. Our primary aims were to evaluate participant characteristics, compare outcomes between participants and nonparticipants, and assess variability of PRP between centers and medications.

Results. The national proportions of PRP at 1 year by organ were kidney (8.2%), liver (2.9%), heart (5.0%), lung (2.6%), and simultaneous pancreas/kidney (2.8%). Factors associated with PRP included recipients' educational attainment, insurance, race/ethnicity, gender and age, donor age, transplant number, income, distance to center, and center volume. Graft and patient survivals were significantly higher among PRP for kidney, liver, and lung transplant recipients. PRP varied markedly between centers (range, 0%–58%) and by immunosuppressant medications.

Conclusions. There are systematic differences between participants and nonparticipants in research in the transplant population that may affect the external validity of research findings. Superior outcomes among participants may suggest that participation in research itself affords certain benefits. Future research evaluating the mechanisms for differential participation rates and improved survival among participants is needed.

1 Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio.

2 Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, Ohio.

3 Department of Bioethics, Cleveland Clinic, Cleveland, Ohio.

4 Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio.

5 Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.

6 Department of Cardiothoracic Surgery, Cleveland Clinic, Cleveland, Ohio.

7 Department of Hepato-Pancreato-Biliary, General Surgery and Transplant Surgery, Cleveland Clinic, Cleveland, Ohio.

This work was supported by a grant from the PhRMA Foundation.

The authors declare no conflict of interest.

The data reported here have been supplied by the Minneapolis Medical Research Foundation as the contractor for the Scientific Registry of Transplant Recipients (SRTR). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy of or interpretation by the SRTR or the US Government.

8 Address correspondence to: Jesse D. Schold, Ph.D., Department of Quantitative Health Sciences, 9500 Euclid Avenue, JJN3-01, Cleveland Clinic, Cleveland, Ohio 44195.

E-mail: scholdj@ccf.org

J.D.S. participated in research design, writing of the manuscript, performance of research, and data analysis; L.D.B. and T.R.S. participated in research design, writing of the manuscript, and performance of research; D.A.G., S.M.F., D.M., J.F., B.R.S., and V.K. participated in writing of the manuscript and performance of research; and E.H. participated in writing of the manuscript, performance of research, and data analysis.

Received 10 January 2011. Revision requested 25 January 2011.

Accepted 8 March 2011.

There are many factors that may influence patients' participation in medical research. These factors may include patients' physical and cognitive ability to comply with research requirements, explicit predefined inclusion or exclusion criteria of studies that often eliminate “high risk” patients, patients' familiarity, and trust of the healthcare system and whether providers have active research protocols (1). Sociocultural perceptions, beliefs, and practices of caregivers may influence the decision to offer participation in studies to patients. The informed consent process including both the type and method of dissemination of documentation may influence patients and their surrogates' decision-making to participate in research (2–4).

There are several reasons why evaluating participation in research is important. One is to understand the external validity of findings that derive from studies. Discordance of baseline characteristics of patients who do and do not participate in research may lead to findings that are not representative of the underlying population and ultimately less applicable in practice (5, 6). As participation in research may provide important opportunities or benefits to patients, in addition to those derived from standard treatment, unwarranted exclusions may also be deemed unethical (7–9). Lack of timely participation in trials may also lead to significant delays in trial completion and less-rapid application of findings into practice (10).

A recent study in oncology cited a 2.5% participation rate of patients in clinical trials and lower rates among minority patients (11). Studies have sought to identify barriers and specific motivational factors that impact research participation including specific focus on vulnerable and high-risk patients (12–15). Empirical research suggests that the complexity of the informed consent process is a primary barrier to participation (16–18). Among a population of dialysis patients, Israni et al. (19) demonstrated that participation in trials was more common among younger patients, nonsmokers, and patients with fewer co-morbid conditions. Studies in HIV/AIDS have documented lack of participation in research because of suspicions about drug interventions, patients not adequately informed of the opportunity to participate, and logistical obstacles such as travel, self-care, and financial obligations (20, 21). In contrast, the therapeutic misconception, which take part in clinical research will directly provide benefits, is often cited by patients as motivation for enrolling in studies (22–24).

To date, there is little research investigating participation in research in the solid organ transplant population. In a single-center study, Brennan et al. (25) evaluated characteristics and outcomes of living donor kidney transplant recipients and found that participants in clinical trials were disproportionally male, had more clinic visits, but had similar outcomes as nonparticipants. The primary aim of this study was to evaluate participation in research among kidney, liver, heart, lung, and simultaneous pancreas/kidney (SPK) transplant recipients using a national cohort of patients. Specifically, we sought to (a) evaluate characteristics of patients who participate in research protocols, (b) compare outcomes of participants versus nonparticipants in research protocols, and (c) examine variation in participation between centers and type of immunosuppression. Findings of this study may be important for interpreting the external validity of research, evaluating factors associated with participation that may promote future interventions, and potentially increase enrollment, and determining whether there are systematic differences among patients who participate in research.

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RESULTS

The study population consisted of solitary kidney (n=112,237), liver (n=36,623), heart (14,372), lung (n=7669), and SPK transplant recipients (n=10,867). The proportion of patient participation by organ and individual donor and recipient characteristics are displayed in Table 1. As indicated, multiple characteristics were significantly associated with participation for each transplant type. The overall proportion of recipients who were reported to participate in research was 8.2% for kidney, 2.9% for liver, 5.0% for heart, 2.6% for lung, and 2.8% for SPKs.

TABLE 1

TABLE 1

Factors that were statistically significantly associated with greater likelihood of participation among kidney transplant recipients in the multivariable models included males, age 18 to 65 years, primary transplants, higher educational attainment, private insurance, living donor recipients, higher median income, non-diabetics, lower panel reactive antibody percentage, and preemptively transplanted recipients (Table 2). Among liver transplant recipients, factors that were significantly associated with higher likelihood of participation in the multivariable model included younger recipient age, primary transplants, lower median income, closer distance to center, and primary diagnoses (Table 3). Factors associated with higher participation among heart transplant recipients in the multivariable model included male adult and Hispanic recipients, primary diagnoses, primary transplants, higher educational attainment and income, and shorter distance to the center (Table 4). SPK participants were more likely to be non-African American, have more educational attainment, and have insurance other than Medicare (Table 5). The Hosmer-Lemeshow tests indicated adequate goodness of fit for each of the models. We did not construct a multivariable model for lung transplant recipients as there was only one factor that was statistically significantly associated with participation in univariable analyses.

TABLE 2

TABLE 2

TABLE 3

TABLE 3

TABLE 4

TABLE 4

TABLE 5

TABLE 5

Based on Kaplan-Meier plots, kidney (log-rank P<0.001), liver (log-rank P=0.02), and lung (log-rank P=0.01) participants in research had better long-term patient survival than those who did not. These associations were consistent in the multivariable Cox models in which patients who did not participate in research had statistically significantly worse survival among kidney (adjusted hazard ratio [AHR]=1.14, 95% confidence interval [CI]: 1.05–1.22), liver (AHR=1.25, 95% CI: 1.05–1.49), and lung (AHR=1.45, 95% CI: 1.11–1.90) transplant recipients (Table 6). For the same organ transplant groups, the hazards for overall graft loss were also statistically significantly worse among nonparticipants. There was no marked variation in the effect of participation within subgroups of the recipient population. The improved survival among kidney, liver, and lung participants remained statistically significant excluding patients at centers with no reported participants and after adjustment for the participation rate by center.

TABLE 6

TABLE 6

The distribution of participation rates by transplant center aggregated across organs are displayed in Figure 1. Among the 279 transplant centers included in the study population, 29% of centers reported no participation in research and 43% of centers reported less than 1% of participants. One center reported 58% of patients participating in research studies and 13% of centers had more than 10% participation. There was a significant positive correlation between transplant center volume and the proportion of patients participating in research studies (r=0.34, P<0.001).

FIGURE 1.

FIGURE 1.

Participation varied by type of baseline immunosuppressive medication among each of the transplant populations (Fig. 2a–e). Among kidney transplant recipients, there was higher participation among recipients using cyclosporine, thymoglobulin, and sirolimus at baseline and reduced participation among patients on tacrolimus, steroids, mycophenalate mofetil (MMF), campath, and interleukin (IL)-2 receptor blockers (RB). Among liver transplant recipients, patients on steroids at baseline were less likely to participate than those who are not on steroids. Among heart transplant recipients, participation was greater among patients on cyclosporine and sirolimus and reduced among patients on tacrolimus, MMF, thymoglobulin, campath, and IL-2 RB. Lung participants were less likely to receive MMF or campath at baseline, and SPK transplant recipients were less likely to receive thymoglobulin or campath.

FIGURE 2.

FIGURE 2.

FIGURE 2.

FIGURE 2.

FIGURE 2.

FIGURE 2.

Missing levels during the period of mandatory reporting for participation (through 2005) ranged from 0.2% to 2.2%. The proportions of participation in this period were all within 1% of those reported for the full study population for each organ. Factors associated with participation were generally consistent with the exception that several factors lost statistical significance. The qualitative results of the survival models were also similar in this subset for each organ type, the AHRs for 1-year conditional patient survival limited to the mandatory reporting period for kidney, liver, and lung transplant recipients were 1.08, 1.24, and 1.46, which all remained statistically significant.

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DISCUSSION

The primary findings of the study are that (a) there are systematic differences between participants and nonparticipants of research protocols for immunosuppressive medications among transplant recipients, (b) outcomes are superior among patients who participate in research protocols for kidney, liver, and lung transplant recipients, and (c) participation in research protocols is largely clustered within certain transplant centers and variable by type of immunosuppression medication. Cumulatively, this study suggests that findings from research studies may not be clearly generalizable to the broader transplant population.

Consistent with other healthcare contexts, both demographic characteristics and indicators of patient acuity were associated with patient participation in research (1, 5, 6, 26, 27). Among kidney transplant recipients, participation was associated with markers of higher socioeconomic status such as private insurance, elevated household income, and greater educational attainment. Reduced participation among pediatric and elderly patients, repeat transplant recipients, diabetics, recipients of older age donors, and sensitized patients may indicate that findings from research studies may be less applicable to patients with higher acuity or special treatment requirements. Despite studies highlighting reduced access to care among African Americans kidney transplant patients, there was not a significant difference in participation after adjustment for other characteristics (28, 29). In contrast, African Americans were less likely to participate in research among SPK transplant recipients, which also has documented access disparities (30). Interestingly, higher income was associated with a diminished likelihood to participate in research among liver transplant recipients who may reflect differences in socioeconomic status between end-organ patients or in the type of research studies between transplant populations. For both heart and liver transplant recipients, patients' distance to the transplant center was associated with reduced likelihood to participate, which is consistent with studies demonstrating that the logistical considerations may explain both participation in studies and outcomes (31, 32).

The elevated survival among kidney, liver, and lung transplant recipients who participated in research may have different implications. First, findings derived from clinical trials or other research studies may be a reflection of a healthier cohort of patients. This may be a product of intentional selection of patients more or less likely to exhibit a particular endpoint and exclusion criteria that may not be captured by variables available in this study. Another potential interpretation of these findings is that participation in research itself affords certain benefits. Superior outcomes may derive from various trials effects such as more rigorous monitoring by caregivers, free or discounted care or medications, beneficial interventions in which patients are participating in research protocols, the Hawthorne effect or changes in patient or caregiver behavior.

Results indicated that a minority of patients participate in research for immunosuppressive medications. Sources of this low participation rate requires further study but importantly results indicate that participation is largely clustered by transplant center. Almost one third of centers report having no participants and 13% of centers report at least 10% of recipients in research protocols. This variation was in part explained by center volume, with a significant association between larger centers and participation. If in fact the superior outcomes associated with participation are explained by enhanced levels and access to care, these findings may explain one of the mechanisms by which large centers generally have better outcomes (33, 34). Sponsors of research may be attracted to centers with a larger volume of patients as well as centers with better outcomes. Wide variations in participation at different centers may be salient to decision-making for prospective transplant patients interested in research (35). Center clustering of participants may question whether research studies completed at selected centers are necessarily applicable to smaller centers or those that do not have research protocols. Results also raise interesting questions about the impact of ongoing research and evaluated quality of care between centers. Differences in participation may not only be an indicative of better quality of care at centers with active research but could also be viewed as a potential source of bias for comparing center outcomes with and without active research programs (36–38).

There is substantial variation in participation in research based on the type of baseline immunosuppressive medication for recipients. This is not surprising given that medications have been available at different stages of approval over the study period through the Federal Drug Administration and that industry sponsors have variable number of active research protocols. Differences in participation by baseline medications may be important to interpret outcomes from observational studies. For instance, studies that compare medications that typically include both participants and nonparticipants may affect results comparing regimens. Further validation of outcomes by medication may also be important to understand the potential external validity for each individual therapy in a research versus a nonresearch context.

There are several important limitations that may impact inferences from our study. First, the measure of participation may be imprecise. It is likely that documentation of participation in research is a sensitive metric (i.e., patients who were noted to participate actually did); however, it may be less specific and patients who participated may not have been noted. This may tend to dilute results with respect to comparisons of patient characteristics and outcomes. It is not as likely that there is a systematic bias in reporting for certain patient characteristics, but the overall proportion of participants may be underreported. Also, based on reporting at 6 and 12 months, we had to exclude patients who had graft loss within 1 year of transplantation. This may impact outcomes in either direction as early events may be more disproportionally distributed among participants and nonparticipants. Participation and outcomes are also likely affected by underlying characteristics of patients who are not available for risk adjustment. For example, patients with non-codified comorbidities may be less likely to be considered viable for participation and the degree of this effect is not known. Finally, there is a wide variety of types of “research studies” (e.g., investigator-initiated or phase I-IV trials) and no documentation available for this study for why patients did not participate in research or providers failed to enroll select patients. These questions require further study with more detailed information.

Each of the differences evaluated in this study (patient characteristics, survival outcomes, center variation, and immunosuppressive therapies) suggests some lack of external validity of research studies as they would be applied to the broader transplant population. Some of these differences may be relatively minor and do not necessarily invalidate the qualitative generalizability of studies. However, it is important to recognize that patient groups with lower participation in studies may not benefit from research findings to the same degree as those populations that more commonly participate (39). Prospectively, well-designed studies that have broad inclusion criteria may be important to this field to understand the external validity of interventions and to minimize the risk for study results that are not applicable in practice (10, 40). Further research is also needed to determine whether differences in participation are based on consent processes, justified or invalid inclusion, and exclusion criteria, and derived from provider or patient preferences or patients' access to care.

In summary, participation in research protocols among transplant recipients varies significantly by patient characteristics, transplant center, and individual medications. Long-term outcomes are superior among participants versus nonparticipants among kidney, liver and lung transplant recipients. Further understanding of the mechanism for differential participation, whether findings suggest disparities in access to care, and the implications for the interpretation and implementation of research findings into practice is needed.

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MATERIALS AND METHODS

We used data from the Scientific Registry of Transplant Recipients (SRTR). The SRTR data system includes data on all donor, wait-listed candidates, and transplant recipients in the United States, submitted by the members of the Organ Procurement and Transplantation Network (OPTN). The Health Resources and Services Administration, US Department of Health and Human Services, provides oversight to the activities of the OPTN and SRTR contractors.

The study population consisted of recipients of a solitary kidney, liver, heart, or lung transplant and recipients of SPK transplants between the years 2000 and 2008. Patients were excluded if they were recipients of multiple organ transplants other than SPK. To classify patients as participants or nonparticipants in research protocols, we used information from OPTN recipient follow-up forms. Recipient forms include a field indicating whether patients have participated in research protocols for immunosuppressive medications during the applicable follow-up period. For the purpose of this study, we classified patients as participants if they were denoted as such at the 6-month or the 1-year follow-up period. To appropriately compare the likelihood of participation and outcomes between patients who did or did not participate in research, we excluded patients with less than 1-year follow-up or graft loss before 1-year or missing information in both follow-up periods.

Missing reports of participation ranged from 5.8% among SPK transplant recipients to 8.6% among lung transplant recipients. This proportion of missing levels increased over time likely based on the fact that the field for reporting participation changed from mandatory to optional after 2005. Therefore, as a part of sensitivity analyses to assess whether missing reports changed the qualitative results of the study, we repeated analyses restricted to the period of mandatory reporting.

Using census data and recipients' primary reported zip code, we added two additional patient characteristics to data collected in OPTN forms. We included estimated household income based on zip code level information and distance to the transplant center based on patients' permanent residence to the zip code of the center calculated by the Statistical Analysis Software (SAS) function zipcitydistance. We used multivariable logistic models to assess the likelihood of participation among recipients for each individual solid organ type. For model covariates, we included both demographic characteristics of donors and recipients consistent across organs along with patients' primary diagnoses for each form of end-stage organ disease and additional variables that were considered relevant markers of patient acuity. The Hosmer-Lemeshow test was used to test goodness of fit of these models. We generated Kaplan-Meier plots and multivariable Cox proportional hazard models for overall graft loss (defined as graft loss or death) and patient death, both conditioned at 1-year overall graft survival. Proportionality of the Cox models was assessed by visual inspection of the residual plots and testing the interaction with follow-up time for the primary explanatory variables. To ascertain whether the effect of participation was affected by participation rates at individual centers, we also used models adjusted for the proportion of participants within each center. Certain immunosuppressive medications were grouped: all formulations of cyclosporine (generic or brand name) were combined and IL-2 RB (simulect or zenapax) were placed in the same group. All analyses were conducted in SAS (version 9.2; SAS Institute Inc., Cary, NC).

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ACKNOWLEDGMENTS

This study was approved by the Cleveland Clinic Institutional Review Board.

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Keywords:

Clinical trials; Participation; Informed consent; Graft survival; Immunosuppression

© 2011 Lippincott Williams & Wilkins, Inc.