Something`s Gotta Give

There is a lot of promising research in the field of heart failure (HF) therapy and management, and Christopher O’Connor, MD, professor of medicine at Duke University in Durham, North Carolina, feels more clinicians should commit themselves to clinical trial investigation, and clinical trials need changes in recruitment and methodology.

One bright spot: pathophysiology and targets for therapy are better understood today; there are now thousands of molecules that can be potential targets to improve treatment of HF. What we’re challenged on today, according to Dr. O’Connor, is a lack of progress in clinical trial methodology, including identifying the correct patient population and recruitment.

As of April 2012, there were 1,075 open studies of HF patients listed in the NIH database, including studies from 179 countries participating in the registry. Dr. O’Connor noted that half of these will never finish because of recruitment problems, while many of those that do finish will be underpowered to answer the original question.

The Trial That Almost Wasn’t

 To illustrate his point, Dr. O’Connor used the multicenter Surgical Treatment for Ischemic Heart Failure (STICH) trial that included a comparison of medical therapy alone with medical therapy plus CABG in patients with CAD and LV dysfunction. He coauthored this study and The Duke Clinical Research Institute coordinated all aspects of global trial operations, site management and monitoring, data collection, statistical analyses, and reporting. The STICH trial demonstrated no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary endpoint of death from any cause. However, patients assigned to CABG had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes, compared with those randomized to medical therapy alone.

Those are the facts of the trial as published; less well-known is the rocky road the investigators took to get there. After 6 years, STICH turned out to be the largest cardiovascular surgical trial ever conducted, with final data from127 sites in 26 countries. However, the average enrollment was about two patients per site per year. Only 22 sites joined the study in its first year and 44 sites were deactivated due to no enrollment—at a cost of about $10,000 per site. Overall, 20% of principal investigators (PIs) failed to enroll a single patient and 30% of PIs under-enrolled.

Originally, STICH was to be a US and Canadian study, but failure to get the necessary enrollment almost
doomed the trial. Without international expansion, Dr. O’Connor said, the STICH trial would never have been completed. In a clinical trial sense, he noted, this experience suggests it simply will not be possible to answer crucial questions regarding exciting new therapies if patient enrollment is like that seen in the STICH trial. It’s not just this single trial, either—38% of PIs who participated in clinical trials between 2000 and 2005 did not return to conduct another clinical trial. They quit, he said, due to the burden of conducting clinical research.

In the end, STICH was a one-of-a-kind, highly successful trial that will unlikely be repeated unless the burden of conducting research changes.

How Can We Fix This?

 The NIH is committed to finding better ways of doing phase II trials using networks, a process that is already working in HF research, with the second 7-year phase ongoing in the Heart Failure Network. This is being done via committed personnel, standardization of processes and core labs, and a real emphasis on using the community and academic centers to recruit.

One model for this approach is an active consortium known as the Duke University Cooperative Cardiovascular Society (DUCCS), which has been doing research since 1990. At the heart of the program are 100 former Duke cardiology fellows who are all committed to community-based clinical research. They have similar training and large patient populations. Dr. O’Connor asked, “What if every academic medical center used their former fellows to form a consortium across the globe? We’d have a large network to enroll patients in clinical trials.”

In other disease states, social media is being employed; an Internet site called PatientsLikeMe, which has signed up almost 150,000 patients listing more than 1,000 different conditions. The site is a reservoir of patients who can participate in studies and includes a clinical trials matching tool; plus, it conducts surveys of registrants that can be useful in trial design. Another site has taken its cue from a dating website, but rather than lonely singles, participants are volunteers willing to learn more about clinical research studies.

Moving Forward

 There is a growing interest in point-of-care trials that occur throughout a health system, by which the admitting provider medical team is essentially “the study team” and the electronic medical record “the data management.” This is currently being done in the Veterans Health Administration, which is the largest integrated health care system in the country. Currently, individuals being admitted to the VHA are asked about being randomized into one of several different strategies of insulin management. The study infrastructure, in this case, is the health system.

Larger numbers of enrolled patients and simpler trials should be the goal, said Dr. O’Connor, pointing to the ASCEND-HF trial, a study of 7,141 patients with acute decompensated HF that confirmed that nesiritide is safe but has no significant benefit on mortality. ASCEND-HF was the largest acute HF trial and the enrollment rate exceeded expectations, in part because it was straightforward, with few inclusion/exclusion criteria. Other studies should seek such simplicity, he said, “We can’t have case report forms with a number of pages that are larger than the number of events.” There is also, he added, a great need for studies that will produce meaningful, real-world outcomes. In ASCEND-HF, this was achieved with the commitment of more than 800 investigators at 398 sites in 30 countries. Usually, he said, the United States lags behind in enrollment, but in this simple pragmatic trial, US investigators enrolled 2,767 patients—38.7% of study participants.

“The future will require a global international trial structure with standardized processes, standardized protocols, and a network of committed investigators to answer questions,” Dr. O’Connor said. For example, a stable international trial structure would have a data safety and monitoring board; steering committees for phase II and phase III trials; site management organizations; and data and statistical centers overseeing centers using standardized protocols, a manual of operations, endpoints, and definitions. This would require a commitment to prioritize studies to ensure full enrollment and appropriately large size with rapid recruitment, likely using novel approaches to patient recruitment.

Political and ethical issues need to be addressed too, to answer questions such as:

  • Due to limited resources, what kinds of trials are worth doing—or worth doing more—than others?
  • What kinds of patients and what categories of disease should be targeted in these trials?
  • Who ought to pay for them?
  • From whose budget should the funds come?

Dr. O’Connor noted that the goals of clinical trials have inescapable political dimensions because of the choices that must be made. Trials have to be made simpler and less costly if we’re going to reach the goals that are possible given basic research advances.Translating these advances to clinical practice, however, will not be possible without new ways of conducting larger and less expensive clinical trials.

Keywords: Volunteers, Veterans Health, Insulin, United States Department of Veterans Affairs, Financial Management, Electronic Health Records, Registries, Patient Selection, Heart Failure, Hospitalization, Biomedical Research, Research, Natriuretic Peptide, Brain

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