Early in the 21st century, after years of study and clinical work, mental health clinicians and investigators in the Veterans Health Administration (VHA) helped to develop and validate the success of two highly effective treatments for veterans with post-traumatic stress disorder (PTSD). The first, prolonged exposure therapy, involves a patient’s vivid and repeated recollection of a traumatic event, until the emotional response to the event is diminished. The idea is for the patient to gradually extinguish overwhelming emotions associated with the traumatic memory.
The second treatment, cognitive processing therapy, works in a similar way. With the guidance of a therapist, patients are taught to evaluate and change the upsetting thoughts they’ve had since their trauma – and in turn, to change their emotional response to these thoughts. This type of therapy, developed in the 1980s by an investigator who later joined the VHA, involves the appraisal of patients’ memories, dialogue, and introspection, and teaches coping skills to challenge negative or upsetting thoughts.
While investigations have provided solid evidence that both prolonged exposure (PE) and cognitive processing therapy (CPT) are effective, there isn’t much evidence to indicate which might have better results. A study comparing them would require a sizeable cohort of PTSD patients who have access to both treatments within a large integrated health care system, staffed by clinicians and investigators experienced in both treating PTSD and in recruiting, planning, coordinating, and executing a large, randomized, multisite clinical trial.
The VHA – the largest integrated health care system in the United States, serving more than 9 million veterans at more than 1,200 health care facilities – may well be the only organization in the United States positioned to do this, in large part due to the experience, resources, and expertise of its Cooperative Studies Program (CSP), a division of the VHA’s Office of Research and Development. The CSP is internationally renowned for its large-scale, innovative clinical trials and epidemiological studies.
In 2014, VA Cooperative Study #591, Comparative Effectiveness Research in Veterans with PTSD (CERV-PTSD), began comparing PE and CPT outcomes among 900 male and female veterans with PTSD related to their military service. As investigators record and process the results of this study, they expect it to advance PTSD care by providing conclusive information about whether one treatment is better than the other – overall, and for different types of patients.
Since it was formally established in 1972, the CSP has conducted large, multicenter clinical trials such as CERV-PTSD – studies aimed at evaluating the effectiveness of medical, surgical, or behavioral interventions – as well as observational epidemiological studies, which evaluate causes or risk factors for disease. According to Grant Huang, PhD, MPH, director of the CSP, the VA actually established the use of multisite cooperative study within the United States. At the conclusion of World War II, when about 10,000 American veterans suffered from tuberculosis, the VA partnered with the United Kingdom’s Medical Research Council (MRC) in evaluating the effectiveness of streptomycin and other drugs in treating the disease. This study, the first VA-armed forces clinical trial, was conducted at seven VA and two military hospitals. “The U.S. and British were trying to tackle the problem of tuberculosis in returning veterans,” said Huang, “and at the time, we had clinicians, scientists, and biostatisticians who came together and said, ‘Let’s rigorously study what treatments work best.’ That became known as a cooperative study.”
One of the most famous VA cooperative studies was launched nearly two decades later by Dr. Edward Freis: the first multicenter, double-blind, randomized placebo-controlled trial to determine the effectiveness of antihypertensive drugs in preventing or delaying serious cardiovascular events and organ damage. The study was conducted among more than 500 patients at 17 centers, and the success of the trial earned Freis a Nobel Prize nomination. He has been referred to as the father of the first multisite clinical trial of cardiovascular drugs.
On the heels of this landmark study, the VA officially established the CSP in 1972, and charged it with coordinating multicenter clinical trials that evaluated novel therapies or new uses for existing treatments. In its first decade, the basic form of the program took shape, with the establishment of CSP Coordinating Centers and a Clinical Research Pharmacy Coordinating Center.
“Since the 1970s,” Huang said, “we’ve developed some new capabilities – for example, in addition to clinical trials, we also conduct large-scale observational studies.” In the late 1990s, the CSP established four Epidemiological Research and Information Centers (ERICs) for this purpose. Prior to VHA launching a genomic medicine initiative in 2006 to advance knowledge of how genes affect health and how medicine might be personalized for veterans, the CSP established a DNA bank and a biospecimen repository to support genomic studies within its trials. This effort helped form the foundation of the Million Veteran Program (MVP), the world’s largest biobank of genetic material, to anchor studies comparing genes, survey responses, and health records of 850,000 veterans (and counting). To date, the MVP has provided the basis for numerous studies of the risk factors for PTSD, Gulf War illness, substance use disorder, cardiovascular disease, macular degeneration, anxiety disorder, and others – as well as for pharmacogenomic studies, or studies of how patients with certain genetic profiles respond to different medications.
From its origins in the 1940s, the CSP has completed more than 200 studies, and today conducts trials at more than 80 VA medical centers around the country. CSP investigators and their partners have evaluated treatments for a variety of conditions, including psychiatric disorders, cancer, neurologic disorders, infectious diseases, diabetes, and cardiovascular disease. These multicenter trials are conducted in partnership with other VA investigators as well as university affiliates, private-sector partners in the pharmaceutical and biotechnology industries, and government agencies such as the National Institutes of Health (NIH) and the Department of Defense. CSP has also partnered internationally to conduct studies with investigators in the United Kingdom, Canada, and Australia.
Two distinct research branches, focused on clinical trials and observational studies, have evolved in parallel within the CSP. Randomized clinical trials are the purview of five CSP Coordinating Centers, located at VA medical centers in Boston, Massachusetts; Hines, Illinois; Palo Alto, California; Perry Point, Maryland; and West Haven, Connecticut. These centers provide study design, data management, statistical analysis, quality management, and administrative support to cooperative studies performed by VA investigators. “These five Coordinating Centers are teams of experts who can design, manage, and run clinical trials, and all the things involved with that,” said Huang. “They have project managers, quality assurance experts, research administrators, and some clinicians as well. They receive the data from all our study sites, and there is a group of statisticians who analyze the data and clean it to make sure the quality is good.”
A unique feature of the CSP is its Clinical Research Pharmacy Coordinating Center (CRPCC) in Albuquerque, New Mexico, which participates in CSP studies involving drugs or medical devices. “I don’t know of any major federally funded center that handles what they do,” Huang said. “They have a lot of capabilities.” CRPCC experts develop drug-handling protocols, negotiate with pharmaceutical companies, distribute and keep track of drugs used in trials, and work with the Food and Drug Administration (FDA) to ensure regulatory compliance. They can also, Huang said, manufacture drugs for use in certain trials, as well as look-alike placebos. The CRPCC’s excellence has earned it an international reputation; in 2009, its rigorous quality assurance protocols earned it a Malcolm Baldridge National Quality Award – and it remains one of only two federal agencies to have won the honor.
Observational research among veteran populations is conducted and disseminated by the CSP Epidemiology Centers, located at VA medical centers in Boston; Seattle, Washington; and Durham, North Carolina. A fourth recently established center in Palo Alto, California, also has expertise in genetic data and analysis. These centers also work with a pharmacogenomics laboratory located in the Little Rock, Arkansas VA medical center. Experts at these centers provide scientific expertise, data, and research infrastructure to conduct large-scale epidemiological evaluations of veterans’ health and disease burdens. They also, Huang pointed out, create and maintain data resources to support VA research. “Our Boston center is the hub of the Million Veteran Program,” he said, “so they collect data about health behaviors and lifestyle from now more than 800,000 veterans, get information from their medical records, and then tie it to the genetic data we’re collecting from their blood.” The Seattle center maintains the Vietnam-Era Twin Registry, a collection of data gathered from studies and biospecimens of more than 14,000 Vietnam-era veteran twins and more than 3,400 selected family members, the largest of its kind. The Durham center specializes in the health effects of Gulf War service, and the Palo Alto center focuses on studies of pharmacogenomics.
Much of the CSP’s work is funded through the VA Office of Research and Development’s (ORD) intramural funding program: Eligible VA clinician investigators come up with an idea for a study and submit a description to Huang’s CSP headquarters in Washington, D.C. After a review, staff at one or more of the Coordinating Centers design and develop a study and launch it through the VA health care system. This same basic process happens for both clinical trials and observational studies. “Both our trial centers and our epidemiological centers will work with clinical investigators to fully develop a quality study or protocol,” he said. “They’ll design the study. They determine how they would recruit the veterans, how many they need, where they would get them from, and then how they would collect their data. Furthermore, they will determine the logistics and other requirements for conducting the study within the VA health care system. And then they analyze it and produce results with our clinical investigators.”
CSP often partners with the Health Economics Resource Center, a facility formally aligned with ORD’s Health Services Research and Development Service, to analyze the cost-effectiveness of a treatment or intervention – whether a drug that performs well might save the VA money, for example, or might be more effective than existing treatments over the long run.
One current clinical trial, CONFIRM, is the largest single clinical trial in VA history, evaluating the two most common types of colorectal cancer screening among 50,000 veterans. CONFIRM is expected to provide definitive guidance on the best methods for colorectal cancer screening to prevent death. The CSP’s ability to conduct trials on this scale benefits veterans, the VHA, and clinical practice everywhere. The most obvious benefit for veterans is that these large-scale trials offer access to cuttingedge diagnostics and treatments, administered by skilled clinicians who are tuned in to their needs.
“A major benefit of our program,” Huang said, “is that we provide definitive evidence that influences health care decisions.” A landmark VA study, conducted in the 1980s, showed that aspirin can reduce heart attacks, and CSP studies have helped establish clinical practice guidelines for treating several other diseases and disorders.
The scope of the VHA also enables the CSP to partner with numerous public and private partners. A collaboration with Merck & Co., a pharmaceutical manufacturer, evaluated the effectiveness of a new shingles vaccine among 39,000 veterans and other patients at 16 VA medical centers, the NIH, and five universities. “We performed the definitive trial,” Huang said, “and our partnership with Merck led to the ultimate approval of the shingles vaccine by the FDA.”
The VHA is uniquely suited to form such partnerships and conduct trials because it is both a research and a clinical care institution. Most research organizations aren’t able to have a direct impact on patient care, Huang said. “They fund scientists and investigators, and they publish. Afterwards, they don’t have the capability [to help patients] because they don’t have the other components that we have. We’re taking advantage of the fact that we have, all within one health care system, the capability to conduct research and provide clinical care, policy, and decisionmaking, and we’re trying to capitalize on those capabilities.”
GETTING MORE VETERANS INTO CLINICAL TRIALS
By participating in VA clinical trials, veterans – particularly those with conditions beyond the reach of routine clinical care – are given access to potentially life-saving or life-enhancing treatments that wouldn’t otherwise be available. This is one of the primary reasons why increasing veterans’ access to highquality clinical trials has been identified as a strategic priority in the VA’s 2021 budget proposal.
Despite the many advantages enjoyed by the VHA’s research and health care system, its scope sometimes presents challenges to external partners, and veterans remain underrepresented in clinical trials funded by non-VHA organizations. Clinical trials conducted at VHA sites tend to take longer than at non-VHA centers, for several reasons. Another significant challenge for partners, said Huang, is simply that the VHA has different ways of doing things – and that these differences are not system-wide, but can vary from center to center.
Huang envisions the CSP as the key facilitator for these potential partners, helping them negotiate these differences and ease the way toward greater veteran participation in multicenter clinical trials. “We’re developing a process where we say, if you’re an external partner in industry or maybe even another federal agency, we will work with you to help navigate our system: figure out what you need to work and coordinate with multiple VA medical centers, and then provide access for veteran patients to clinical trials of, let’s say, new drugs or new therapies that industry might want to be testing or developing. So that’s now a more externally focused set of priorities that we’re dealing with.” This external focus will necessarily specialize, like CSP’s overall structure, along two parallel lines, for both industry and federal partners.
One template for how the CSP might increase opportunities for veterans emerged in the summer of 2018, when the VA formed a partnership with the National Cancer Institute (NCI): the NCI and VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE). “NAVIGATE was actually based on a model we developed at CSP for recruiting within the VA for CSP studies,” said Huang. When the NCI reached out to VA to encourage more veteran enrollment in cancer trials, the CSP shared this model with them. “And they said, ‘We want to do that, too. Can we fund a group of sites using that model, but then be more focused on NCI-funded trials?’”
Under the NAVIGATE partnership, the NCI is building infrastructure at 12 VA sites for clinical trials of cutting-edge cancer therapies, including precision medicine therapies based on patients’ genetic profiles and immunotherapies that channel patients’ own immune systems to fight the disease. Similar partnerships may be in the works, Huang said; the National Institute on Aging (NIA) has approached the CSP about a partnership focusing on diseases of aging, such as Alzheimer’s. Another NIH organization, the National Center for Advancing Translational Sciences, has discussed teaming up to enhance the work of NIA’s PREVENTABLE trial (Pragmatic Evaluation of Events and Benefits of Lipid-Lowering in Older Adults). “They have a network of university-based sites,” Huang said. “And VA has about 60 sites where we’re going to contribute to this large-scale, 10,000-patient study looking at the effect statins have on dementia.” CSP and the NIA are discussing ways in which the two might share ideas, expertise, and practices.
When he speaks of “expertise,” Huang points out that he’s not just talking about scientific and clinical expertise; CSP has developed decades’ worth of expertise in every aspect of large, multicenter clinical trials: operations, finances, administration, safety, and the rigorous technical and regulatory standards involved in planning, coordinating, and conducting trials that may involve tens of thousands of veteran participants. “This whole initiative,” he said, “is about leveraging that expertise, to be part of a larger national clinical research enterprise and do studies that will really benefit veterans – and all Americans, for that matter.”