The 21st century dawned with the promise of cell therapy for the treatment of cardiovascular disease. Beginning in 2002, with Orlic’s animal model work demonstrating the potential benefit of autologous cells on left ventricular (LV) function in animals,1 additional work2–4 demonstrated that both procedures and cells were safe enough to justify human clinical trials of bone marrow mononuclear cells5–9 to improve cardiac function.
These studies and a resulting meta-analysis10 showed that cell therapy, when carefully delivered and monitored, could be safely studied in humans. The promising findings of this early work drew the attention of the National Heart, Lung, and Blood Institute (NHLBI), which called for the creation of a research network, with the principal mission of investigating the safe and effective use of cell therapy to treat cardiovascular disease in humans.11
Background
This air of optimism was threatened by the headwinds of recruitment failure. Many clinical trial managers spanning all fields of medicine were unable to randomize sufficient numbers of subjects to reach their goals.12 A survey of Lancet and The British Medical Journal revealed that in 2000–01, almost 60% of published trials either required an extended period of time beyond what was expected to complete recruitment or outright failed in the effort.13
Extensive reviews of mailing and web-based strategies, incentives, and other strategies have produced disappointment.14 Some investigators in frustration invoke Lasagna’s Law,15 which states that “the number of patients eligible for a study will decrease during the study period by a factor of ten and returns to normal following completion of the trial period.”
Many clinical trial teams are now uncertain as to what to do other than “the best that one can”; some have reduced to reporting recruitment problems in the hope that this will help to devise strategies to overcome the problem.16 So grim is the situation that overt concerns are now appearing about the longevity of clinical trials as a viable research paradigm.17
Meanwhile, the germinal cell therapy field had its own collection of controversies. The 1990s opened to the great promises of gene therapy; however, the Jesse Gelsinger case at the University of Pennsylvania highlighted the potential for serious lapses in reporting prior research experience, safety monitoring, and conflicts of interest.18
Simultaneously, a sharp rise in the number of adverse event reports to the U.S. Food and Drug Administration (FDA) occurred, and the number of drugs withdrawn from the market increased, tightening the focus on safety oversight. In 2003, the FDA temporarily halted 27 gene therapy trials using retroviral vectors in blood stem cells in the face of new leukemia-related syndromes in two children.19 Some had even called for a moratorium on cell therapy clinical trials.20
Lagging recruitment efforts in combination with the early failures of gene therapy produced a challenging combination, threatening the success of cell therapy clinical trials designed to study subjects with acute myocardial infarction (AMI). By itself, AMI produces a challenging patient population known for rapid onset of symptoms, a “non-patient” frame of mind for subjects and family who are commonly told that they have been cured by primary percutaneous intervention (PCI), and the short window to consent and acutely treat subjects.
This article describes the recruitment techniques, tools, and lessons learned and used by the Cardiovascular Cell Therapy Research Network (CCTRN) to successfully recruit and follow subjects in its two AMI trials.
CCTRN Organization and Recruitment
CCTRN Clinical Structure
Funded by the NHLBI in 2007, the CCTRN was formed in an effort to combine the knowledge and expertise of researchers at multiple clinical centers with the unified goal of investigating the safety and efficacy of cell therapy in cardiovascular heart disease.21 It included five clinical centers, a cell processing quality control laboratory, five core laboratories, the NHLBI Project Office, and the Data Coordinating Center (DCC).
CCTRN AMI Trials
CCTRN investigators designed two trials (TIME and LateTIME) to address the effect of cell therapy on LV function in subjects with large AMIs, and whether the intervention’s timing influenced that effect.22–25
TIME randomly allocated cell therapy to Day 3 or Day 7 post primary PCI; in LateTIME, cell therapy was delayed by two to three weeks. Following bone marrow aspiration, cell processing, and delivery, patients were followed for six months when both LV function and clinical outcomes were assessed.
Original Enrollment Predictions
The original recruitment plan in 2008 predicted a gradual increase to a total of five randomized subjects per month across all centers. Follow-up data from the earlier 18-month BOOST trial8 were used to calculate the sample sizes of 120 in TIME and 87 in LateTIME. BOOST’s recruitment rate was an average of approximately two patients per month over 15 months, using a single center for enrollment.
We conservatively estimated the following rates: five patients per month across five centers, beginning with two patients per month for three months and increasing by one patient per month every three months. Thus, it would take nine months to accelerate to five subject randomizations per month.
Enrollment Experience
The first subjects were consented into TIME in July 2008 and into LateTIME in September 2008. All five main centers were actively screening subjects for both trials by November 2008. Consolidated standards of reporting trials (CONSORT) diagrams for each study have been published.26,27
Challenges to the enrollment predictions were clear within a year. Each of the two studies averaged two randomizations per month through May 2010, with a significant drop to 0.6 randomizations per month from August 2009 through December 2009 in TIME, after a brief FDA-prompted administrative hold. The Steering and Executive Committees initiated an in-depth review of the protocol, including inclusion/exclusion criteria and screening data, to ascertain the barriers at each center and satellite site.
Site-Reported Recruitment Barriers
In a retrospective review of the 3,651 subjects screened, 515 patients met all inclusion/exclusion criteria and thus were eligible to be enrolled for the AMI studies. Among the eligible patients, we had a high enrollment refusal rate of 53%, or 275 individuals. For more than half of these patients (144), no specific reason for declining to participate in a study was identified (see Figure 1). Even with 2:1 (active: placebo) allocation, 5% (13) of subjects declined due to the possibility of receiving placebo. Additionally, 5% (13) declined due to “family issues.”
Figure 1.
Reasons Eligible Patients did not Consent (N = 275) (n, %)
Profound challenges were posed by TIME’s requirement for subject randomization to either the three- or seven-day intervention group within two days following their AMI. The research coordinators noted that in these patients with a first MI, neither the subject nor the subject’s family understood the disease nor appreciated the gravity of its long-term prognosis. Explaining a new AMI diagnosis and its implications—as well as potential research opportunities as complex as cell therapy—was particularly challenging for research teams within the short timeframe of the study.
During this time, CCTRN research coordinators learned that family members were more influential in the consenting process than was anticipated. Therefore, to address the strong influence of families (positive or negative), coordinators and physician investigators included family members in conversations with potential study candidates from the beginning of the recruitment process. During these helpful discussions, family members cited risk of procedures, chance of placebo, and potential extended hospital stay as the most common reasons to decline.
Recruitment Methods
Based on these observations, the CCTRN undertook a multifaceted approach to improve recruitment.
Protocol Amendments
Two protocol amendments that included removal of low-risk exclusion criteria and the inclusion of patients with large non-anterior MIs were made after extensive discussion.
Satellite Centers
An earlier publication on the CCTRN satellite experience is available.28 Although some satellite centers performed well, others failed due to their inability to complete the considerable administration start-up tasks, or to recruit and successfully follow the expected number of patients.
To aid with participation, satellite physicians were assured that subjects would be directed to return for ongoing clinical care both during and following completion of the trial, and were invited to observe study procedures.
The ability to predict which satellites would be the best performers and which would be noncontributory was a challenge for the network’s managers. Infrastructure funds for satellite staff support were crucial.
At the conclusion of the study, satellite sites proved to be a very valuable addition to the network by enrolling 33% of the subjects in the two trials.
Recruitment Action Plans
The Recruitment Committee contained at least one representative from each main and satellite site, as well as representation from the DCC and NHLBI, and held monthly teleconferences. Each site representative was responsible for developing and implementing a site-specific recruitment action plan, including monthly and quarterly recruitment goals for each protocol, implementation plans to combat barriers to recruitment, and outreach opportunities to initiate in the community.
DVD and Brochure
A professional medical graphic company produced an educational DVD consisting of three modules scripted from the protocol and informed consent form. The coordinators designed the modules to be teaching tools for patients and families about normal functioning of the heart, why AMIs occur, potential chronic heart changes, and details regarding participation in the CCTRN studies. The DVD was also effective at teaching floor nurses, cardiology fellows, and community groups about the studies.
DVD players were provided to each clinical center so that coordinators could show the DVD to patients during the consenting process and leave it at the bedside to educate family and friends. DVDs were also available for the patient to take home. Additionally, a four-color, tri-fold brochure was developed to provide similar information in a different format using information consistent with the DVD.
From creation to site distribution, the DVD and brochure production process took approximately six months, with final approval at all sites by May 2010.
Online Presence
The CCTRN’s Internet presence was strengthened so that potential participants and healthcare providers could easily find information about the CCTRN studies online in several different venues.
Results
A general description of the data is provided using frequency counts and percentages. Statistical testing was conducted in order to assess whether demographic subgroups (e.g., women) were over or underrepresented in consented or randomized populations.
Recruitment goals were met for both trials. The average randomization rate before the recruitment plan was 1.7 and 1.9 subjects/month in TIME and LateTIME, respectively. After the implementation of all aspects of the recruitment initiative, the rates increased to 4.0 and 4.2 randomizations per month in TIME (p < 0.001) and LateTIME (p = 0.032), respectively.
Recruitment differed by sex. Of the 515 eligible subjects, 112 were females (22%). Of the 240 consented subjects, 37 were females (15%), and of the 275 eligible subjects who declined, 75 were females (27%), resulting in a significant difference between the percent of eligible females who did and did not consent (p = 0.001).
We therefore evaluated sex differences for each of the reasons subjects declined. All 13 patients who “did not want placebo” were male (p = 0.0227). Of the 13 subjects who reported “family issues,” nine were female and four were male (p = 0.015). No other categories differed significantly by sex.
Figure 2 illustrates various aspects of the recruitment initiative and the influence on trial recruitment. Although it took an average of only four weeks for local institutional review boards to approve amended protocols required by a short FDA clinical hold, this had a lingering effect lasting months on recruitment. The network used the downtime to reevaluate enrollment and recruitment strategies through the establishment of the Recruitment Committee and site recruitment action plans.
Figure 2.
Recruitment Charts
A modest recruitment surge occurred in both trials when the DVDs and brochures went to the sites, though more for LateTIME, since these patients had more time to consider enrollment. Other increases in recruitment in the trials occurred either directly before or after the in-person Steering Committee meeting, dubbed the “Steering Committee Effect.”
Randomizations averaged about four patients per month in months with in-person meetings, but only about 2.5 patients per month without in-person meetings. NHLBI guidelines29 were used to guide discussions. In addition, coordinator participation steadily increased at the in-person meetings following new funding for coordinator travel, which facilitated open discussion and motivation to keep recruitment a priority at the sites.
Figure 2 also plots the monthly subject recruitment for both AMI trials (TIME and LateTIME) from the trial onset to completion.
Discussion
The CCTRN completed two complex, placebo-controlled clinical trials on budget and within the grant cycle. The recruitment effort required open minds that could objectively assess performance and make necessary changes to enhance recruitment without compromising trial design. The principal lesson the network learned in recruiting in this tempestuous environment, surrounded by failures of clinical trial recruitment in other fields, is that multifaceted approaches work best.
Also, the continued active participation of the recruitment center leadership was essential to meet clinical trial goals. The total commitment of principal investigators to the recruitment efforts of their centers is transmitted in myriad ways to recruitment team members, leading to their spirited action and resultant improved recruitment rates.
Coordinators worked hard to identify subjects, while principal investigators and coordinators labored together to explain the study to prospective recruits. Regardless of educational materials, the presence of satellite sites, or changes in inclusion/exclusion criteria, recruitment effort is a “ground game” with solid effort required for each new subject.
The CCTRN AMI studies yielded several important lessons. Investigator involvement is vital for recruitment, especially when novel interventions are involved. Solid and complete screening data are required, and available under the Health Insurance Portability and Accountability Act.30
Recruitment for the AMI trials presented barriers, but also generated solutions that produced successful completion of the studies (see Table 1). Several important lessons from the CCTRN recruitment experience should be transferable to other multicenter clinical studies (see sidebar).
Table 1.
Recruitment Barriers
| Barriers to Recruitment | Countered by |
|---|---|
| Placebo arm randomization | Education on clinical trials |
| Patients felt well post PCI and/ or lacked understanding of the medical event (AMI) | Education on the disease process |
| Family member’s influence | Involve them in the consent process from the beginning |
| Perceptions of stem cells (political, religious, media, etc.) | Education on stem cells |
| No compensation for travel or lodging/“too far” to travel | Education on clinical research |
| Short time to randomization made referrals from outside centers very challenging | On-call system and flexible coordinators and principal investigators |
| Advanced ST-segment elevation myocardial infarction programs reducing door-to-balloon times | Capitalizing on the patients who did come in the door and were eligible |
Recruitment of women and minorities continues to be a priority for CCTRN. We found fewer females and minorities were recruited than nonminority males. A clear understanding of the prevalence of women and minorities with AMI is important, and focused strategies to recruit these patients must be developed that account for cultural and gender-based factors related to consent.
A recent study by Brown and colleagues31 found that direct letters with an ethnically targeted statement about health risks were significantly more effective for recruiting minorities than generic or personalized letters. CCTRN may improve its recruitment of underrepresented minorities with this approach.
Logistical issues for patients (e.g., transportation distance costs) were major impediments to recruitment and deserve more consideration in developing trials. Educational materials were also important in this trial. Visual aids were well received by potential subjects and families, with the DVD being extremely valuable in explaining the disease process, research process, and trial details. Satellite networks expand the reach of the trials and boost enrollment.
In addition, CCTRN research coordinators identified the unanticipated, gender-specific force of persuasion. When the subject was a male, the subject’s family was more likely a positive influence on the subject’s entry into the study. However, when the subject was female, the familial influence was reversed, with the woman’s family more likely being neutral or actively against their loved one’s participation. This suggested that approaches might be tailored to the different types of arguments families raised to oppose the subject’s trial involvement.
Encouraging collaboration and allowing sites to create tailored recruitment plans was invaluable. Site staff know their population best and how best to serve it. Input from coordinators and investigators on customized recruitment strategies equated to sharing ideas and learning best practices that were very helpful. Ongoing communication and interaction among members of the entire network cannot be overemphasized in achieving enrollment goals.
Facilitators to Recruitment.
Trust established at first point of contact with potential subject
Collect the right screening data
Communication among sites facilitated “best practice” discussion and dissemination
Education on stem cells and coronary artery disease diagnosis by research coordinators
Family members involved in the consent process
In-person Steering Committee meetings
Educational materials (DVD and brochures)
Investigator involvement
Enhanced Internet presence
Protocol amendments for expanding inclusion criteria
Involvement of potential subject’s attending physician prior to approach
Patient reimbursement for travel and lodging
Address randomization head-on
Crossover study design
Site-specific recruitment plans
Acknowledgments
The research coordinators who recruited patients were instrumental to the success of these CCTRN trials. We would like to thank the following for their hard work: Beth Jorgenson, RN, CCRC; Barb Bruhn-Ding, RN, CCRC; Emily Caldwell, RN, CCRC; Klaudija Dragicevic, RN; Tempa Curry, RN, CCRC; Carrie Geither, RN; Judy Francescon, RN; and Sherry Bowman, RN. The funding for this trial was provided by the National Heart, Lung, and Blood Institute under cooperative agreement 5 UM1 HL087318.
Footnotes
Disclosure
There were no reported conflicts of interest by any authors.
Contributor Information
Rachel E. Olson, Minneapolis Heart Institute Foundation. She can be reached at rachel.olson@allina.com.
Rachel W. Vojvodic, University of Texas School of Public Health-Houston, and a project manager with the Cardiovascular Cell Therapy Research Network (CCTRN). She can be reached at rachel.w.vojvodic@uth.tmc.edu.
Judy Bettencourt, University of Texas School of Public Health-Houston, and one of three project managers for the Data Coordinating Center supporting the CCTRN. She can be contacted at Judith.l.bettencourt@uth.tmc.edu.
Eileen M. Handberg, Cardiovascular Clinical Trials Program in the Division of Cardiovascular Medicine at the University of Florida, as well as an associate professor of medicine, institutional review board member, and Cardiovascular Division representative on the College of Medicine Continuing Medical Education Committee. She is also program director for the practitioner competency assessment program called Florida CARES. She can be reached at Eileen.Handberg@medicine.ufl.edu.
Elizabeth Szymanski, Florida Hospital Tampa, Pepin Heart Institute. She can be reached at elizabeth.szymanski@ahss.org.
Deirdre Smith, Stem Cell Center at Texas Heart Institute, as well as the president of the ACRP Greater Houston Chapter. She can be reached at dxsmith@texasheart.org.
Jody LaRock, Special and Intensive Cardiac Care units of United Hospital, part of Allina Health. She can be reached at jody.larock@allina.com.
Shreela V. Sharma, Division of Epidemiology at the University of Texas, School of Public Health. She can be reached at Shreela.V.Sharma@uth.tmc.edu.
Doris A. Taylor, Regenerative Medicine Research at the Texas Heart Institute. She co-directs the CCTRN Biorepository and leads a cell and cytokine profiling core lab that serves multiple NHLBI networks, medical centers, and research foundations in the U.S. and Canada. She can be contacted at dtaylor@texasheart.org.
Timothy D. Henry, Cedars-Sinai Heart Institute in Los Angeles, Calif. He can br reached at henryt@cshs.org.
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