What a difference a decade makes. In the late 1980s and early 1990s, the viability of pediatric rheumatology seemed in doubt. Few fellows were being trained, and medical centers were fortunate if they had even one pediatric rheumatologist on staff. The paucity of trained pediatric rheumatologists created severe access problems for children with disorders like juvenile idiopathic arthritis (JIA) and pediatric lupus. Depending on where they lived, children needing care for a rheumatic disease might be treated by an adult rheumatologist—or no rheumatologist at all.
Looking at pediatric rheumatology from an academic perspective, research was difficult because many of the diseases are rare and affected children live all over the country and are unable to receive care at research centers. Christy Sandborg, MD, had just moved to Stanford University (Calif.) as a pediatric rheumatologist, and she was worried. “Even though you could do important research in a laboratory, I wondered what good it would do without access to the kids who had these diseases,” she says.
Support from several pharmaceutical companies allowed additional meetings over the next 18 months, during which time CARRA’s guiding principles and an initial scientific agenda were defined. Some members of the fledgling group, which soon included 30 pediatric rheumatologists, determined how projects would be vetted through the network, while others worked on organizational structure, criteria for membership, and short- and long-term financial strategies. “The time was ripe because a critical mass of pediatric rheumatologists had developed,” explains Dr. Mellins. “This is a young field, only started in the 70s, and we had the second and third generations working at the time of the membership drive. Pediatric rheumatologists knew the questions they wanted answered: What was the natural history of these diseases? The causes? The impact on children’s lives? The best way to treat them? But they were working in isolation, without enough patients to study, but also without enough time, resources, or clinical research experience to translate their ideas into robust research projects.” The first abstract based on CARRA research was entitled, “Barriers to participation in clinical research within the US pediatric rheumatology community,” which appeared in 2002 in a supplement to Arthritis & Rheumatism and underscores her point.1
The initial CARRA strategy was to support members by identifying grant opportunities and providing both a ready group of collaborators with patient populations and the scientific endorsement of the appropriate experts within CARRA. A critical step forward was the first two-year contract from the AF, “to find out if we could to go from our blueprints to a working organization,” says Dr. Mellins. The AF has been a consistent source of core financial support for CARRA since 2002.
CARRA Today
“CARRA is important because the diseases we are interested in are relatively rare. One center can’t do a definitive study with the limited number of patients there. CARRA enables 300 investigators at 92 sites to pool resources, synergize, recruit the required number of patients, and do rigorous research,” says Norman T. Ilowite, MD, chair of CARRA and professor of pediatrics at the Albert Einstein College of Medicine in the Bronx, N.Y. While PRCSG continues to do industry-sponsored studies, he says, CARRA concentrates on investigator-initiated research.
“These diseases have analogues in adult medicine, but others are distinct and restricted to children,” Dr. Ilowite says. “And the patients are different, with developmental and nutritional factors that we need to account for. Most of the time, a treatment that is safe and effective in adults is also safe and effective in kids, but the dosing, pharmacokinetics, and pharmacodynamics can be quite different. You can’t always extrapolate from adult data very well.” He also explains that because pediatric rheumatologic diseases are relatively rare, pharmaceutical companies have little financial incentive to do definitive studies in children in diseases other than polyarticular juvenile idiopathic arthritis (JIA).
“CARRA was formed to fill a void in investigator-initiated research, which was quite limited 10 years ago. CARRA has a very democratic and transparent philosophy and is very inclusive. We can do the research that we conceive of and can get funded,” Dr. Ilowite adds.
CARRA research currently focuses on six areas: juvenile arthritis, pediatric systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), vasculitis, scleroderma, and pain and health-related quality of life. CARRA members have identified specific agendas for each of these areas. A small sampling of these agenda items includes
- Developing trials to determine the best treatment approaches for all JIA types and assessing the long-term safety and efficacy of the immune modulating, suppressive, and biologic agents used to treat JIA;
- Developing studies to understand the assessment and treatment of kidney involvement in pediatric SLE;
- Developing studies that will evaluate treatment approaches in JDM;
- Developing therapeutic interventions for children with chronic rheumatic and nonrheumatic musculoskeletal pain; and
- Identifying the most effective means of studying the course and outcomes of vasculitis and scleroderma in children.
“With CARRA, we are bringing research to more patients,” says Laura Schanberg, MD, professor of pediatrics at Duke University in Durham, N.C., and one of the physicians who has been with CARRA since its earliest days. CARRA has already successfully completed two major clinical trials and many other smaller studies supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the AF. As Dr. Schanberg says, “we haven’t yet reached as many as we’d like, but our long-term impact is really greater than the studies we’ve done to date. We’ve developed the infrastructure to facilitate clinical research and to try to advance an agenda that is not formed by industry alone.”
To date, at least 11 CARRA studies and 16 abstracts have been published. Recently, findings of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) appeared in Arthritis & Rheumatism, and this study, sponsored by NIAMS and, although the study is closed to enrollment, tissue samples can be used for ongoing translational studies and novel ways of looking at the data are being pursued.2 Dr. Ilowite notes the seminal trials of early aggressive therapy in JIA, and a study of the safety and effectiveness of rilonacept in systemic JIA. See Table 1 for a complete listing of CARRA studies.
The CARRA Registry
Building on CARRA, the organization of pediatric rheumatologists, is CARRAnet, the network of sites where these investigators work. The first project for CARRAnet is the CARRA Registry, an observational retrospective and prospective cohort study enrolling pediatric patients with major rheumatic diseases who are being followed at participating study sites. But with human and financial resources strained at individual sites, CARRA has had to find outside means to support this endeavor.
“We would like to be able to add, as an organizational support, more infrastructure that is directly usable by sites and that will help them accomplish research. We have done that to some degree with the CARRAnet grant, which was awarded by the National Institutes of Health (NIH) with funds from the American Recovery and Reinvestment Act (ARRA) of 2009,” says Dr. Schanberg. The funds, totaling over $6 million, will enable CARRAnet to bolster its informatics capabilities at individual sites, allowing them to enter patients in the CARRAnet registry. The grant was awarded to Duke University, where Dr. Schanberg one of the lead investigators along with Dr. Sandborg, Dr. Ilowite, and Carol Wallace, MD, at Seattle Children’s Hospital. The grant is administered by the Duke Clinical Research Institute (DCRI).
The goal of CARRAnet is the creation of a unifying, scalable informatics infrastructure for CARRA sites. According to DCRI senior project leader Kathleen Fox, the infrastructure currently under development by CARRAnet will increase operational efficiencies at each CARRA site. “You systematically build on operational processes you agree to at the beginning, and these become less burdensome as you add more projects,” says Fox. “For example, we’ve developed master site agreements. The basic legalese is already agreed upon. When there is a new project, we just add an addendum, rather than renegotiating right from the beginning,” she says. Funding for the CARRAnet grant continues through August 2011 with the possibility of an extension through August 2012.
In addition to the assistance that sites receive for setup and inclusion in the CARRA registry, the sites will also benefit from the fact that CARRAnet data will be federated, which means that sites will soon be able to access their own data without a gatekeeper, and compare them with data from other sites. Targets for the CARRAnet grant include the eventual participation of 60 sites with 20,000 subjects. The first CARRAnet site was activated in May 2010; 52 sites are currently active, and more than 3,000 subjects have been enrolled in the registry. According to Dr. Schanberg, there is an even split among CARRAnet centers that have extensive research experience, some research experience, and no previous experience, demonstrating that all types of centers can successfully participate in bringing research to more children with rheumatic diseases.
“It is incredibly gratifying to work with such a dedicated group of physicians,” Fox says. “They are truly passionate about what they’re doing, and that makes the whole team passionate about making CARRAnet work and building the structure we need to make a difference in the life of these kids.”
Building an Identity
The creation of CARRA helped pediatric rheumatologists in another way—by forging an identity for these physicians as a community pushing the field forward. The CARRA meetings—one held concurrently with the ACR Annual Scientific Meeting and a second, stand-alone meeting—have become forums for working groups that focus on pediatric diseases, like juvenile arthritis and pediatric lupus. “The disease-specific groups have developed into effective teams, and when the CARRAdx and CARRAnet grants came through, they were ready to go to work,” says Dr. Mellins.
“This year the CARRA meeting is in Miami,” says Dr. Schanberg. “We’re partnering with the PRSYM [Pediatric Rheumatology Symposium] meeting of the ACR. We expect more than 200 people, and this will be a working meeting,” she says. Among other projects, members will be developing consensus treatment protocols so that care of children with these diseases is standardized. “We also want to standardize the outcomes we look at, so that we can do comparative effectiveness research,” notes Dr. Schanberg.
A Guiding Light
Although they initially looked to several organizations as models, the founders of CARRA are unabashed in their admiration of one particular pediatric treatment network: the Children’s Oncology Group, which started as two groups that eventually merged. “They demonstrated a culture in which the standard of care is for each child with cancer to get placed on a protocol. A current treatment approach is tested against the best idea for a treatment that might be even better. As a consequence, in 20 years, the treatment approaches to childhood cancer have evolved and improved in a data-driven way,” says Dr. Mellins. She adds that recent decreases in childhood cancer mortality provide compelling evidence for this model of care.
As a community, we decided that every child with a rheumatic disease should have access to participation in a protocol, a registry, a clinical trial, or an observational study.
—Christy Sandborg, MD
The lesson was not lost on CARRA members. “As a community, we decided that every child with a rheumatic disease should have access to participation in a protocol, a registry, a clinical trial, or an observational study,” says Dr. Sandborg. “We believe that making research a standard of care would allow these children access to the best treatments.” Dr. Schanberg agrees, noting that in the APPLE trial, in which children with SLE were randomized to receive atorvastatin or placebo, all children also received standard care consisting of hydroxychloroquine and aspirin. “Some of the study sites were not routinely using hydroxychloroquine, and now they do. There are data that this is a best practice,” she says, adding that this demonstrates how study participation has the potential to improve patient care.
As is the case with pediatric cancer research, “the CARRA effort is strongly driven from the family side,” says Dr. Sandborg. “They go on the web, see the protocols, and seek out the best treatments. The vast majority of parents want to do something for their kids and those like them.” Even when enrollment in a trial may not directly help their own child, most parents continue to participate, hoping that the research may benefit other children with the same disorder. “Sometimes this is a hard sell,” says Dr. Sandborg, again citing APPLE. “APPLE is not a primary treatment trial—we’re trying to prevent a complication that might occur 10 or 20 years down the road. But enrollment rates for that trial were unusually high, which speaks to both to the relationships between physicians and patients, but also to partnerships among families on behalf of children.”
The Next 10 Years
In the next few years, Dr. Sandborg would like funding for CARRA to be less episodic. “We want to keep moving forward in a sequential manner, going from one step to the next in learning to treat a disease. We want sites functioning on CARRA projects at all times so that when a study is ready to go, all a site has to do is move some pieces around,” she says. CARRA is currently funded by NIAMS, Friends of CARRA, the AF, the ACR, The Wasie Foundation of Minnesota, the Lucile Packard Foundation for Children’s Health, and some pharmaceutical companies.
According to Dr. Sandborg, nearly 100% of all pediatric rheumatologists in the U.S. and Canada are members of CARRA. Fewer than 10 adult rheumatologists are members, but CARRA hopes to enlist more, especially from areas underserved by pediatric rheumatologists. The eventual goal would be to establish a means by which adult rheumatologists in areas not served by pediatric rheumatologists could reach out to CARRA for the resources needed to treat children. A closely related goal is to create a network of affiliates. For example, a CARRAnet site in Denver could support children in a neighboring state that doesn’t have a pediatric rheumatologist. A CARRA physician could partner with an adult rheumatologist in the other state to create a research opportunity, provide access to the CARRA registry, and find studies relevant for the child. “It’s a huge effort. We care for half of all kids with rheumatic diseases, and we want to care for the rest of them, too,” says Dr. Sandborg.
Toward this goal, CARRA is developing a culture of research. “We know that there is not a sufficient evidence base right now to say for sure what the best care is for children with these diseases. It’s only when a group of people decide to treat in a certain way that you can gather the data to figure this out,” Dr. Schanberg says.
Dr. Ilowite adds, “We would like to have cures for some of these diseases affecting children. I think in the next few years we will have agents to control the diseases, and that it is realistic to expect some cures. We strive to cure.”
Mary Desmond Pinkowish is a medical journalist based in New York.
References
- Giannini EH, Wallace CA, Brunner HI. Barriers to participation in clinical research within the US pediatric rheumatology community. Arthritis Rheum. 2002; 46 (suppl.):S310. Abstract #779.
- Schanberg LE, Sandborg C, Barnhart HX, et al. Premature atherosclerosis in pediatric systemic lupus erythematosus: Risk factors for increased carotid intima-media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort. Arthritis Rheum. 2009;60:1496-1507.
