Author + information
- Received October 29, 2018
- Revision received February 3, 2019
- Accepted February 4, 2019
- Published online April 29, 2019.
- Mitchell A. Psotka, MD, PhDa,∗ (, )@mpsotka,
- Susan E. Ammon, RN, MS, FNPb,
- Mona Fiuzat, PharmDc,
- Biykem Bozkurt, MD, PhDd,
- Eugene S. Chung, MDe,
- Robert T. Cole, MDf,
- Stephen J. Greene, MDc,
- David Kraus, MDg,
- Bonnie Ky, MD, MSCEh,
- Colleen K. McIlvennan, DNP, ANPi,j,k,
- Palak Shah, MD, MSa,
- John R. Teerlink, MDl,m,
- Mary Norine Walsh, MDn,
- Mariell Jessup, MDo and
- Christopher M. O'Connor, MDa
- aAdvanced Heart Failure, Inova Heart and Vascular Institute, Falls Church, Virginia
- bSan Francisco, California
- cDuke Clinical Research Institute, Durham, North Carolina
- dDivision of Cardiology, Winters Center for Heart Failure Research, Baylor College of Medicine, Houston, Texas
- eCenter for Heart Failure Therapy and Transplantation, The Christ Hospital, Cincinnati, Ohio
- fDivision of Cardiology, Duke University School of Medicine, Durham, North Carolina
- gStern Cardiovascular Foundation, Memphis, Tennessee
- hPerelman School of Medicine, University of Pennsylvania Health System, Philadelphia, Pennsylvania
- iAdult and Child Center for Health Outcomes Research and Delivery Science, University of Colorado School of Medicine, Aurora, Colorado
- jColorado Cardiovascular Outcomes Research Consortium, Denver, Colorado
- kDivision of Cardiology, University of Colorado School of Medicine, Aurora, Colorado
- lSchool of Medicine, University of California-San Francisco, San Francisco, California
- mSection of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, California
- nSaint Vincent’s Heart Center, Indianapolis, Indiana
- oAmerican Heart Association, Dallas, Texas
- ↵∗Address for correspondence:
Dr. Mitchell A. Psotka, Inova Heart and Vascular Institute, 3300 Gallows Road, Falls Church, Virginia 22042.
Objectives This study sought to determine clinician and scientist involvement in heart failure (HF) clinical research and to describe the challenges of conducting clinical trials in the United States.
Background Improvements in the current capability, potential, and deficiencies of the HF clinical research infrastructure in the United States are needed in order to enhance efficiency and impact.
Methods The Heart Failure Society of America (HFSA) distributed an electronic survey regarding HF clinical trial activity for the purpose of understanding the barriers that exist to conducting high-quality HF clinical research.
Results Overall, 1,794 HFSA members were queried, and 434 members (24%) completed surveys, whereas a total of 7,589 individuals with interest in HF were queried, and 615 completed surveys. Of the respondents, 410 (67%) were actively engaged in HF research and 120 (20%) were interested in research. Most respondents, 270, were physicians (44%); 311 of the total (76% of the total and 80% of physicians) practiced in academic institutions; 333 respondents (81%) had served as principal investigators and 73 (18%) as site coordinators. Respondents active in clinical research usually participated in 1 to 5 trials and enrolled 1 to 20 patients annually. Institutional review board (IRB) approval typically required 3 months, and contract completion required 3 to 6 months per site. The greatest barriers to research were insufficient site budgets, delay in contracting, inability to find participants meeting trial entry criteria, and unavailability of qualified study coordinators.
Conclusions Many U.S. clinical research sites are constrained by budgetary, staffing, and contractual issues. The HFSA Research Network seeks to unify interested sites and deconstruct barriers to permit high-value HF research.
Heart failure (HF) clinical research has become increasingly difficult to perform in the United States (1). Nevertheless, randomized controlled clinical trials remain the gold standard for studying therapeutic safety and efficacy. Slow enrollment and poor patient and clinician engagement are among the many reasons for high trial costs and diminishing generation of evidence, but the breadth of detriments to the feasibility of clinical research in the United States remains incompletely characterized (2). Health system-based and regional research networks have demonstrated the capability to conduct more efficient clinical investigation and may provide a model to improve research on a broader scale (3–5). The Heart Failure Society of America (HFSA) is a member organization composed of physicians, surgeons, research scientists, nurses, advanced practice clinicians, pharmacologists, and other multidisciplinary professionals. Due to the diverse nature of HFSA membership, which is focused primarily on HF care, organization members were selected as an ideal group to survey. To determine and enhance the capability of the national HF clinical research infrastructure, the multidisciplinary HFSA Research Network Task Force designed and distributed an electronic survey to gain insights into the involvement of HFSA members and others in HF clinical research and to describe the challenges of conducting clinical trials in the United States.
Survey design and population
This cross-sectional survey of clinicians and investigators active in the field of HF was designed to describe the current participation and barriers to performing clinical research in the United States. The primary population included present or past members of the HFSA for whom contact information was available. The extended population included members of the American Heart Association (AHA), the American College of Cardiology (ACC), and industry partners who self-identified as having an interest in HF, for whom contact information was available from their parent organizations. The eligible population consisted of physicians, researchers, nurses, nurse practitioners, pharmacists, pharmacologists, physician assistants, and research coordinators. Eligibility, furthermore, required active or past participation in clinical HF research in the United States as identified by the respondent. SurveyMonkey (San Mateo, California) was used to administer the survey.
From May 2017 to December 2017, self-administered survey data were electronically collected from current or past HFSA members or from members of the AHA, ACC, and industry partners who self-identified as having an interest in HF. The survey was distributed through the HFSA mailing list and associated cardiovascular society mailing lists by electronic mail after a prenotification mailing was sent. Response was monitored closely, and to improve the reply rate, reminders were distributed to the target population 5 times before the study closed. Additional promotion encouraging survey participation was posted on the HFSA website on HFSA Twitter and Facebook accounts and by flyers distributed at the HFSA 21st Annual Scientific Meeting in September 2017.
The HFSA Research Network Task Force designed the electronic survey to describe the involvement of HF-associated clinicians and investigators in clinical research and to record the challenges that impaired conducting clinical trials in the United States. Potential barriers to participation in clinical research and demographic variables that may modify those barriers were initially identified by review of published research. Key stakeholders from the HFSA community, including clinicians and researchers and those with various training backgrounds including physicians, researchers, research coordinators, nurses, nurse practitioners, and pharmacists, were included in the subsequent semistructured focused discussions regarding item generation and reduction, including identifying potential barriers to research participation, as well as for pretesting. The survey underwent extensive pilot testing within the HFSA Research Network Task Force, the HFSA Research Committee, and the HFSA Board of Directors to ensure appropriate content and to improve readability and question clarity prior to full distribution. The survey was designed to require nominal responses (see the Online Appendix for full content).
The resultant survey consisted of 42 individual response items. After survey respondents’ eligibility was determined, they were given questions to assess individual demographics, including whether they were HFSA members, their educational credentials, and practice settings. Subsequent items included type and number of trials conducted per year; annual total patient enrollment; staffing, regulatory, and contracting issues; and use of electronic health records (EHR) for screening. When questions queried respondents’ participation in HF clinical trials or academic productivity, the time frame was restricted to the previous 3 years. All respondents were asked to rank the 8 consolidated potential barriers to high-quality research on an 8-point scale, with 1 being the most important.
Survey results were compiled and analyzed by using descriptive statistics through the SurveyMonkey program and Stata version 14 software (Stata Corp., College Station, Texas). Missing data were treated with pairwise deletion. Rankings were compared by using the Kruskal-Wallis equality-of-populations rank test and by the Wilcoxon rank sum. A p value of <0.05 was considered statistically significant.
Characteristics of survey respondents
The survey was distributed to 1,794 HFSA members and 7,589 total HFSA, AHA, and ACC members and colleagues (Figures 1 and 2⇓⇓). Overall, 23.6% of the mailed surveys were opened by the recipients. Among the 1,794 HFSA members who received the distribution, there were 434 surveys (24%) completed (Figure 1). In total, there were 615 surveys (8%) returned (Figure 2), and the survey typically required a mean of 6 min to complete. Respondents represented 45 U.S. states from approximately 331 distinct private or academic institutions, and there were no more than 14 respondents from any single institution, with 41 institutions having ≥3 respondents. Of the total, 410 respondents (67%) were actively engaged in HF research, including 330 (76%) of the HFSA members, and another 120 (20%) of the total were not currently involved but interested in research opportunities. Physicians comprised the largest group of respondents, followed by nurses or nurse practitioners (Table 1). The proportion of respondents who were physicians was similar among the institutions with ≥3 survey respondents (64%) to those institutions with only 1 to 2 respondents (67%). More HFSA members were physicians (69%) than non-HFSA members (51%). Of those participating in research, most practiced at academic institutions (Table 1), although more HFSA members worked in an academic setting (80%) than non-HFSA members (54%). Of current researchers, 182 (44%) had published more than 5 papers in the previous 3 years. There were 333 (81%) with experience as clinical trial site principal investigators and 73 (18%) with experience as study coordinator. The largest proportion of individual respondents with research experience, 148 (36%), reported employing 2 to 3 HF research study coordinators as part of their research team.
Clinical research experience
A description of the types of trials in which respondents participated in the 3 years before the survey is presented in Table 2. Respondents had most commonly participated in trials of pharmaceuticals for HF with reduced ejection fraction or for HF with preserved ejection fraction or in registries or outcomes research for HF. Of those who participated in clinical research, 230 (56%) reported participation in investigator-initiated clinical trials. Of those involved in clinical trials, most participated in an average of 1 to 5 trials per year (n = 238 [58%]), most commonly enrolling 1 to 20 patients per year (n = 156 [38%]). A sizeable group enrolled between 21 and 50 patients annually (n = 95 [23%]).
Of the 410 who participated in clinical research, 131 (32%) reported association with at least 1 organized research network: 69% with the National Institutes of Health, 30% with the Duke Clinical Research Institute, 16% with the United States Department of Veterans Affairs, 6% with the TIMI (Thrombolysis In Myocardial Infarction) Study Group, and 5% with the Canadian VIGOUR (Virtual Coordinating Centre for Global Collaborative Cardiovascular Research) group. Of the total respondents participating in clinical research, 213 (52%) had served in at least 1 local or national leadership role within a clinical trial, including 152 (37%) as national lead or coprincipal investigator, 102 (25%) on a trial steering or executive committee, 92 (22%) on a data and safety monitoring board, 63 (15%) on a clinical events committee, 31 (8%) as a core laboratory director, and 13 as a national coordinator for a multicenter trial.
Institutional review board and site contracting
Only 183 respondents (45%) active in clinical research reported that it was possible to use a central institutional review board (IRB), whereas only 32 respondents (8%) acknowledged current active use of a central IRB. Most respondents reported it took <3 months to complete local IRB approval (n = 209 [51%]), but 122 (30%) replied that the wait was usually 3 to 6 months. Responses regarding central IRB approval were similar: 145 respondents (35%) endorsed a wait of <3 months for central IRB approval, and 63 (15%) reported a wait of between 3 and 6 months. Contract completion most often took between 3 and 6 months to finalize (n = 156 [38%]), although 121 (30%) replied that it typically required <3 months. Of the respondents active in clinical research, 331 (81%) reported using the EHR to screen for appropriate patients for clinical research, and the most common EHRs used in that group were Epic (Verona, Wisconsin) by 210 respondents (63%) and Cerner (North Kansas City, Missouri) by 77 respondents (23%).
Barriers to site-based research
Respondents ranked the relative impact of 8 perceived barriers to high-quality research (Central Illustration). The most highly ranked impediment to clinical research was insufficient budget relative to the study requirements; 27% of respondents believed this was the greatest barrier, whereas 61% believed it was 1 of the top 3 impediments. When any other topic was chosen as the most important barrier, budgeting was most likely to be chosen as the issue with the second highest impact. Budgetary issues were followed by delays due to legal review or contract completion (15% ranked first), lack of available patients meeting inclusion and exclusion criteria (16% ranked first), inability to hire and retain qualified study coordinators (10% were ranked first), and delays due to IRB approval (6% were ranked first).
Less influential but nonetheless identified by some were inadequate numbers of studies offered and difficulty with data collection, and the least consequential was believed to be investigator experience and oversight. Additional barriers frequently identified by free text response included lack of protected investigator time, specifically with regard to competing clinical productivity pressures; an absence of compensation or salary support for investigators’ trial activities; high academic institutional overhead; poor access to research networks that facilitate research; burdensome trial documentation requirements; and lack of general institutional support or “buy-in” for the research endeavor.
When the respondents’ barriers were compared based on their employer (nonacademic, academic, Veterans Affairs, or industry), there were only minor differences in the overall rankings between academic and nonacademic responses (Table 3). Although more respondents from academic settings ranked insufficient budget as the top barrier (37% ranked first) than nonacademics (15% ranked first), both groups gave the highest mean ranking to budgetary concerns. For respondents from both academic and nonacademic settings, delayed contracting was the second highest ranked barrier. Individuals employed by the Department of Veterans Affairs also ranked delayed contracting and insufficient budget as the top 2 impediments to research, although IRB approval was the next most important issue. In contrast, the respondents from industry ranked the lack of eligible patients for enrollment as the greatest barrier to research, followed by contracting and budgeting.
There were few differences seen between rankings made by principal investigators and study coordinators, with mildly higher importance placed by coordinators on investigator experience (Table 4). There were also only minor differences in rankings made by HFSA members compared to nonmembers (Online Table 1). Clinical physicians and nurses or nurse practitioners participating in research responded with similar ranking schemes, whereas pharmacists ranked the availability of study coordinators and difficulty with data entry higher, and full-time researchers ranked patient eligibility difficulties as the most important concern (Online Table 2).
Using a broadly distributed survey, these authors have demonstrated substantial but incompletely realized clinical trial potential within the HF community. Many experienced and published clinical researchers were identified, as well as some with less previous participation, but all with interest in and enthusiasm for participating in future HF clinical research, and their most common and significant barriers to successful involvement were articulated. Of the total respondents, 92% desired to be or currently were involved in HF clinical trials, and many of them had a resume of success in performing HF research. These diverse current and would-be investigators may be molded into a unified HF research network to generate future evidence in a more efficient manner. This was the intention of the HFSA Research Network: in ongoing work it seeks to establish an integrated and high-quality HF network of investigators committed to conducting high-value clinical research.
To improve HF clinical trial productivity and efficiency, the identified barriers to clinical trial participation and site-based research will require amelioration. The 3 principal limitations to clinical trial participation were insufficient budget to support the trial activities, difficulty with legal and prolonged contracting, and trouble enrolling patients within the confines of trial inclusion and exclusion criteria. Although none of the described obstacles to site-based clinical research will come as a surprise to experienced investigators, this study highlights the need to assuage and overcome these impediments to improve clinical trial efficiency and performance in the United States (1,6). These obstacles permeate all types of research enterprises and infrastructure, as even academic programs, with additional resources including fellows and protected research time, struggle to overcome them (Table 3).
Respondents identified budgetary concerns as the most prominent and influential roadblock impeding clinical trial participation (Central Illustration). Part of this stems from the complicated and costly needs of research sites to hire and maintain coordinators, associates, and other necessary infrastructure, as well as to perform burdensome high-frequency study follow-up visits with substantial data entry. However, much of this budgetary concern appears due to the competing demands of clinical practice and productivity such that research activity is financially undersupported or even discouraged for fellows, faculty, and staff. Thus, these budgetary concerns appear intricately intertwined with the systemic issue of a weakened research culture that has been previously described (7). One potential solution is to design and implement novel clinical trial methods including streamlined and pragmatic trial protocols with decreased workload and cost, such as the TRANSFORM-HF (ToRsemide compArisoN With furoSemide FORManagement of Heart Failure; NCT03296813) (1,8,9). The creation and increased use of standardized case report forms and automated EHR data extraction to reduce manual data entry burden should also aid this process. Finally, reorganized incentive structures can better promote research alongside clinical performance and reinstill a research culture (7). These solutions are complementary.
The second deterrent to clinical research participation most commonly identified was difficulty with contracting. Contracting is not typically engaged in directly by the local site investigators, coordinators, or staff, but rather is performed by attorneys from the potential research site and those from the trial sponsor, typically industry or government, or the involved clinical research organization. Contracts typically seek to ensure appropriately complete data collection; nondisclosure agreements to protect the sponsor’s proprietary information; legal language to comply with local, national, and international rules and regulations; compensation frameworks; publication rights; and indemnification or protection for the research site in case of hazard from the trial (10). This process should be simplified and expedited by the use of central contracting such as an Accelerated Clinical Trial Agreement (ACTA) as a standard template by investigation sites and sponsors (11,12). Unfortunately, institutional uptake of these type of contracting solutions has been slow and remains incomplete.
Inability to find eligible patients for trial enrollment was the third most commonly identified hindrance to clinical trial participation. Although patients with HF are ubiquitous within the U.S. medical system, increasingly complex inclusion and exclusion criteria limit enrollment potential for trial sites (13,14). Again, novel trial designs including the use of more pragmatic and less exclusive criteria for patient selection have the potential to mitigate this barrier while improving the generalizability of trial results (8). More importantly, less restrictive criteria for patient enrollment should appreciably diminish the extensive paid coordinator time needed for patient identification, thereby streamlining coordinator workload and reducing the cost for sites to perform. EHRs also should be used to facilitate patient identification and make clinical trial enrollment more efficient.
Limitations to this survey include a modest response rate at 24% of the HFSA members and 8% of the total survey distribution despite multiple efforts to engage and increase returns. This is in part due to the low proportion of survey mailings that were opened by recipients, despite repeated attempts and alternative promotions, and may also reflect duplicate mailings to recipients included in each of the HFSA, ACC, and AHA member databases. In this regard, the data collected may not be generally representative of all clinical trial site-based research or HF clinicians in the United States. Response to the survey may correlate with interest in HF clinical research, and the results may thus overestimate site enthusiasm for research due to response bias. Additionally, no demographic information was available for nonrespondents, which prevents comparison with the respondent population. As with all surveys, a potential source of error is the inadvertent exclusion of potential survey respondents who did not receive the original distribution. Further potential sources of error include the fact that the data are self-described and cannot be verified, unrecognized systematic biases, and variations may be present in the survey questionnaire.
This survey-based assessment of the current HF research infrastructure in the United States identified opportunities for enhancement and barriers to investigator and institutional participation. It is the authors’ intent that the results of this survey can be used to springboard HF research in the United States into the future by rectifying major current barriers to research participation and, potentially, with the creation of a unified and broad HF research network coordinated by the HFSA. Many of the developments required to solve the most commonly identified impediments to research participation are in the early stages of implementation; however, the research community will need to further use these solutions to improve the current research culture. The HFSA Research Network seeks to achieve those goals by promoting research awareness among clinicians and patients to increase participation; standardizing site training, education, and maintenance to improve quality and performance; creating and promoting a patient-centered HF clinical trial digital warehouse to facilitate patient understanding and interest; and centralizing IRB evaluation, contracting, and budgeting to smooth site initiation. The research community identified and activated with this survey will form the nidus for unification, collaboration, and growth of the network to facilitate high-value HF research.
COMPETENCY IN MEDICAL KNOWLEDGE: Current barriers to enhanced HF clinical research in the United States include insufficient budgets, slow contracting, and difficult inclusion criteria. Modifying those barriers will be necessary to generate needed evidence and improve patient care.
TRANSLATIONAL OUTLOOK: The HFSA Research Network seeks to overcome those barriers and unify trial sites, but ongoing work will be needed to identify new solutions and local and national research champions.
Supported by the Heart Failure Society of America. Dr. Psotka is a consultant for Amgen, Cytokinetics, and Roivant. Dr. Bozkurt has received funding through her institution from Novartis; is a consultant for Amgen and Lantheus; and is a member of the Clinical Endpoints Committee for Abbott. Dr. Ky has received funding from Roche and Pfizer. Dr. Chung is a consultant for Boston Scientific, Medtronic, and CardioMEMS; is a compensated speaker for Boston Scientific; and has received funding through his institution from Gambro, Medtronic, and Boston Scientific. Dr. Greene is supported by National Heart Lung and Blood Institute T32 post-doctoral training grant T32HL069749-14 and a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis; and has received research support from Amgen and Novartis. Dr. McIlvennan has received support from the Heart Failure Society of America. Dr. Shah has received support from Merck and Haemonetics; has received grant funding from Merck, American Heart Association/Enduring Hearts, and Medtronic; and is a consultant for NuPulse CV and Ortho Clinical Diagnostics. Dr. Teerlink is a consultant for Amgen, Bayer, Cytokinetics, Novartis, and Stealth Health; has received funding from Abbott, Amgen, Bayer, Bristol-Myers Squibb, Novartis, and scPharma; has received research grants and personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cytokinetics, Medtronic, and St. Jude; and is a consultant for Abbott, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Cytokinetics, Medtronic, Merck, Novartis, and St. Jude Medical. Dr. O’Connor has received research funding from and is a consultant for ResMed, Merck, and Bristol-Myers Squibb; is a consultant for Stealth Peptides; and is a co-owner of Biscardia. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Barry Greenberg, MD, served as Guest Editor for this paper.
- Abbreviations and Acronyms
- American College of Cardiology
- American Heart Association
- electronic health record
- heart failure
- Heart Failure Society of America
- Received October 29, 2018.
- Revision received February 3, 2019.
- Accepted February 4, 2019.
- 2019 American College of Cardiology Foundation
- O'Connor C.M.,
- Psotka M.A.,
- Fiuzat M.,
- et al.
- O'Connor C.M.,
- Meese R.,
- Carney R.,
- et al.
- Ambrosy A.P.,
- Mentz R.J.,
- Krishnamoorthy A.,
- Greene S.J.,
- Severance H.W.
- O'Connor C.M.,
- Bristow M.R.
- Ford I.,
- Norrie J.
- New J.P.,
- Bakerly N.D.,
- Leather D.,
- Woodcock A.
- Baer A.R.,
- Hohneker J.A.,
- Stewart T.L.,
- Verschraegen C.F.
- Kiriakis J.,
- Gaich N.,
- Johnston S.C.,
- et al.
- Strasser J.E.,
- Cola P.A.,
- Rosenblum D.
- Benjamin E.J.,
- Blaha M.J.,
- Chiuve S.E.,
- et al.