Partnerships to Advance Therapies for Rheumatic Diseases in Children and Adults

March 15, 2013

The overall goal of all NIAMS roundtables is to discuss scientific and clinical needs, and to listen to the concerns and challenges facing the scientific community. These sessions provide a valuable source of input for the NIAMS planning process. This specific roundtable focused on the development of partnerships between industry, academia, and the government to advance therapies for rheumatic diseases in children and adults.

Background

The current major challenge in the treatment of rheumatic diseases is to provide clinicians with tools to rationally choose the most effective and safest therapeutic option for each individual patient. Carefully collected long-term safety data, biomarkers of disease progression, and clinical response are still lacking for many diseases. In order to collect these safety and biomarker data, the community needs large, publicly available databases with prospectively gathered treatment response data and simultaneously collected high-quality biological samples. Funding from the American Recovery and Reinvestment Act was used to create the appropriate infrastructure and demonstrate the feasibility of collecting data from a large group of patients in a systematic way at multiple centers nationwide (Childhood Arthritis and Rheumatology Research Alliance [CARRA]: Accelerating Toward an Evidence-Based Culture in Pediatric Rheumatology; Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository [TETRAD]). While the investigators have engaged in dialogue with representatives from industry and the FDA, and these organizations have expressed enthusiasm about the value of the resources to their own research activities, a more vigorous effort to secure the participation of private sector partners is needed to build on the initial success of the projects. NIAMS is interested in encouraging these interactions and in providing an environment that facilitates a dialogue among the members of the private sector, academic researchers, and regulatory agencies to advance shared goals in the treatment and prevention of rheumatic diseases.

During the 2012 NIAMS Scientific Retreat, the topic of “Leveraging and Strategic Funding Collaborations” was discussed to explore creative strategies to enhance collaborative funding and the development of new partnerships within NIH and with organizations outside of NIH, in order to support innovative and highly relevant scientific projects. NIAMS is interested in ways to expand interactions with the private sector and to collaborate on projects of shared interest. The first goal of this roundtable was to discuss with industry representatives potential partnerships to protect and sustain the support of valuable resources like registries, repositories, and longitudinal cohorts to advance the goal of developing new therapeutics and to comply with regulatory requirements shared by all stakeholders. Validation of biomarkers for rheumatoid arthritis (RA) and evaluation of treatment safety in pediatric rheumatic diseases present important opportunities in this area. Significant and advanced negotiations have taken place between academic researchers supported by NIAMS and industry colleagues working in these two specific areas.

The second goal of the roundtable was to define key areas of high priority that are ripe for new partnerships between NIH, FDA, and industry. The roundtable also identified efficient and effective ways for collaboration among academia, government, and industry.

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the Osteoarthritis Initiative (OAI) were lauded as excellent models for the development of partnerships. Both the ADNI and the OAI were originally funded by the NIH, with additional support coming from the pharmaceutical industry and private foundations, through the Foundation for the NIH (FNIH). Both public and private support are essential to the success of these initiatives, and both are beginning to bear fruit in the area of biomarker identification, which may lead to the development of disease-modifying interventions. A similar model could be developed to collaborate on, for instance, the use of registry data for post-market surveillance in order to determine treatment safety and efficacy, and to better understand rheumatic diseases. It is important to set up the collaborations so that both public and private partners can learn from the available data in the most efficient way possible.

Childhood Arthritis and Rheumatology Research Alliance (CARRA): An Observational Registry for Children with Rheumatic Diseases

Pediatric rheumatologists face numerous challenges. Specifically, there are many medications used for treatment of rheumatic diseases in children, but relatively few patients, leading to questions of long term safety, optimal use, and biologic impact. CARRA, formed in 2001, is a North American organization of pediatric rheumatologists who are committed to advancing the health and quality of life of children with rheumatic diseases and arthritis and who have joined together to answer critical research questions to elucidate the causes of rheumatic diseases in children, determine the best treatments, and track long-term outcomes.

CARRAnet was established with support from the American Recovery and Reinvestment Act as part of CARRA to create a unified, scalable informatics infrastructure and to engage families, patients, and communities in addressing critical clinical research questions. The CARRA registry has currently enrolled over 8,500 pediatric patients at 62 sites. Most of the individuals have been diagnosed with juvenile idiopathic arthritis (JIA). In fact, this is the largest collection of individuals with JIA in the world. Other diseases represented in the registry include: systemic lupus erythematosus (SLE), multiple connective tissue disease, juvenile dermatomyositis, localized scleroderma, systemic sclerosis, vasculitis, and juvenile primary fibromyalgia syndrome. The predominant drug treatments in this group include: etanercept (Enbrel®), adalimumab (Humira®), infliximab (Remicade®), abatacept (Orencia®), anakinra (Kineret®), and tocilizumab (Actemra®).

The CARRA registry can be used for the efficient collection of data to inform post-marketing safety surveillance, therapeutic trials, studies of comparative effectiveness research, the development of consensus treatment plans for a variety of diseases, and observational studies. CARRA CoRe (Consolidated Registry) is an integrated, observational registry that can be used to provide information on long-term safety of therapeutics. It was developed through a public-private partnership with a task force that included representatives from CARRA, several professional and patient advocacy groups, and the federal government. CARRA CoRe provides several advantages, including: the rapid accrual of a large number of patients, long-term follow-up into adulthood, and central coding of all adverse drug events. CARRA CoRe can collect data on all patients exposed to a particular therapeutic, as well as other therapeutics that can be used for comparison purposes. It provides a centralized infrastructure to collect and deliver data. There is a great efficiency of scale because of the large patient population contained in the registry. Additionally, the FDA has approved this model and has expressed a willingness to accept data on drug safety collected by the CARRA CoRe.

CARRA is currently facing several issues which may impact the long-term viability of this resource. CARRA requires sustained funding to provide staff support in the clinical setting to ensure the continued enrollment of eligible patients. CARRA is an excellent resource for companies conducting post-marketing surveillance. The FDA looks for control data to be included in the post-marketing surveillance information and the CARRA registry provides an easily accessible cohort of control data, thereby saving time and financial resources.

The discussion focused on how to create partnerships with companies that might be interested in using the CARRA resources. Industry or foundations could contribute sustaining funding to CARRA which would give them the opportunity to influence the research agenda of the network. These partners would also be able to query the registry when data is needed for post-marketing surveillance studies. There were concerns among the industry participants that CARRA would not be able to answer questions to inform post-marketing surveillance in a timely way in order to meet the demands posed by regulatory requirements. This topic was widely discussed and the industry participants were assured that CARRA would be able to deliver the information needed in a timely manner and would be able to satisfy any regulatory concerns. Utilization and support of the CARRA registry would likely only appeal to those companies which currently market, or are in the development process, for therapeutics to treat pediatric rheumatology patients. Advocacy groups may also be interested in providing support for CARRA since it would ultimately benefit their patients and families.

Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository (TETRAD)

Treatment of RA has improved dramatically in the last 10 years. However, no single drug is effective in every patient, and there is a great deal of variability in both toxicity and price. In addition, there is no way to predict which drug will work the best for a particular individual. TETRAD was established in 2009 with support from the American Recovery and Reinvestment Act to address the need to individualize the use of available therapeutics for RA; to better understand how to stratify patients according to molecular and cellular pathways that may predict treatment response at the patient level, and thereby enable targeted therapy; and to accelerate the discovery of biomarkers of drug response. TETRAD is a large, accessible treatment outcomes database and repository, currently consisting of nine active sites that have enrolled a total of 200 patients, with over 1,700 blood specimens and over 275 radiographs currently in the repository.

TETRAD is unique in that a feasibility pilot was completed before the large scale collection was initiated. The infrastructure can be easily scaled up to include more data collection sites around the country. The investigators drive the research agenda of TETRAD. In addition, TETRAD utilizes state-of-the-art laboratories at the participating institutions that can process biologic materials. The scientific community also has open access to the data and samples stored in the repository. TETRAD data and samples are a valuable resource to address many critical scientific research questions. The continuous collection of cohort data and biospecimens to build a large, publically-accessible registry is crucial to the ongoing success of TETRAD.

The goals for TETRAD going forward are to:

• Provide the scientific community with a large, multicenter, longitudinal database of RA patients starting on biologic agents or methotrexate to answer questions about treatment efficacy and toxicity at the patient level.
• Catalyze efforts of rheumatology investigators at academic medical centers to help provide a resource to enable molecular phenotyping of patients and to stratify them according to the likelihood of treatment response.
• Facilitate the discovery of clinical-grade, marketable tests to predict treatment response to drugs available to treat RA.
• Ensure that there is a research infrastructure that is optimally positioned for future linkage of data and specimens with large-scale electronic health records-based clinical infrastructure.

The current challenges in the treatment of RA include a shortage of good therapeutic options to get individuals into remission; lack of biomarkers to track disease development, progression, and response to treatment; and a limited understanding of the natural history of the disease. TETRAD is crucial to help the research community address these issues.

The discussion of TETRAD also touched on the Biomarkers Consortium which is a public-private biomedical research partnership, managed by the FNIH, that endeavors to discover, develop, and qualify biomarkers to support new drug development, preventive medicine, and medical diagnostics. The goal of the Biomarkers Consortium is to accelerate the development of biomarker-based technologies, medicine, and therapies for the prevention, early detection, diagnosis, and treatment of disease. Industry representatives are also members of the Inflammation and Immunity Steering Committee (IISC), which is responsible for identifying and moving forward promising pre-competitive biomarkers projects for implementation by the Consortium.

Individuals with RA show biochemical heterogeneity in their immune cells and in the signaling pathways that lead to disease development. In addition, there are limited therapeutic options that enable individuals with RA to reach remission. In order to foster new drug development, there is a need to develop appropriate biomarkers to aid in understanding the molecular mechanisms, disease progression, and treatment response. TETRAD can provide the infrastructure and serve as a source for genotypic/phenotypic information so that biological specimens can be studied in a more meaningful way. At the same time, industry needs the assurance that the TETRAD repository will contain the type of data and the biospecimens needed to advance the drug development process. TETRAD has developed a list of critical scientific questions that can be answered using resources available in the repository which could stimulate interest from industry partners, provided that the research could be kept in the pre-competitive space. Several topics were mentioned, including but not limited to: disease heterogeneity, molecular phenotyping, genome sequencing in individuals with rheumatic diseases, peripheral blood sampling, DNA methylation, and studies of the metabolome and microbiome.

TETRAD was established to provide a continuing, well-characterized, well-controlled dataset within the United States. If TETRAD wants to encourage investment from industry, it should consider also collecting biopsy samples. There are already consortia in the United Kingdom and Asia that collect biopsy samples; it was felt that these provide more available data for the investment. It was suggested that a for-profit model (similar to that used in the Consortium of Rheumatology Research of North America [CORRONA]) may be considered to ensure that these registries are available for the longer term. However, it may be difficult for the community to gain access to the information and data in such a registry. TETRAD allows more open access from the public and may therefore be more useful.

Repositories like TETRAD could serve as the impetus to bring industry partners together to fund the infrastructure separately. Once that is in place, TETRAD could approach the FNIH to see if funding is available to continue support of the repository; however, it is important for TETRAD to develop concepts that will interest FNIH. It is also important to engage other stakeholders, including advocacy groups, patients, and their families, and to ensure that there are efforts made to include members from racial and ethnic minorities.

The OAI was described as an example of a fruitful interaction with the FNIH and the Biomarkers Consortium. The OAI was started with the intent to form a cohort of individuals at high risk for developing knee osteoarthritis (OA). However, more individuals were enrolled that already had established OA. The OAI continued to follow these individuals for progression of disease, as well as those at high risk for developing OA, for 4 years. The initiative has recently been extended for an additional 4 years of follow-up. The OAI is currently partnering with the FNIH’s Biomarkers Consortium to search for biomarkers that might predict the progression of disease. The database is open to the public; however, requests to use biospecimens from the OAI cohort must go through a rigorous peer review process.

Opportunities to Develop New Partnerships

The afternoon discussion focused on opportunities to develop new partnerships between academia, industry, and the Federal Government. It is crucial to develop collaborations between and within the public and the private sectors. The acquisition of genotype and phenotype data on patients is essential, as well as access to a variety of tissue samples, including skin tissues for scleroderma and synovial tissues for RA. Large clinical cohorts in which the biospecimens are readily accessible are also needed to enable studies on biomarkers.

The sharing of data from clinical trials is becoming more prevalent. For example, the European Medicines Agency (EMA) held a workshop in 2012 to discuss how to share clinical trial data in a public database while still protecting patient privacy. While the EMA is requesting that all data be publicly available, the practice of many companies is to only share part of the data or to combine datasets to prevent re-analysis of the entire dataset by individuals outside the particular organization. Transfer and analyses of a large dataset require specialized resources, and industry would like to ensure that the outside organizations have the expertise in place to properly analyze the data. With the increased focus on the re-purposing of therapies already on the market, there may be interest in sharing only the control data. Additionally, there are also concerns regarding sharing of data and the consent forms signed by patients upon enrollment into the study. The data sharing procedures must be approved by the Institutional Review Boards and clearly outlined to the patients. In some disease areas, such as lupus, there are major obstacles to developing a large and unified collection of high quality samples and data with open access to the public. It was recommended that NIAMS take on the responsibility of getting the various research groups together with the intent of discussing the best ways to share the data and samples.

The pre-competitive space is another excellent place for industry and academia to collaborate. Pre-competitive space is defined as the period of time when companies can collaborate with other companies and academia, without any concerns for intellectual property. Once research reaches the competitive space, a company’s interests would become paramount and preclude collaboration with other industry partners. NIH supports the basic research which may lead to findings that spark a company’s interest. There should be a mechanism to help fund these pre-competitive projects. For example, the FNIH could be used to develop a consortium of funding support for this type of endeavor.

At this time, CARRA is the best resource for post-marketing surveillance in the rheumatic diseases. As mentioned previously, CARRA would be able to provide the needed data to industry in a readily-accessible form and in a timely manner. Additionally, it might be beneficial to align registries like CARRA with European registries and to provide common definitions and standards of care. There are some concerns with using registries to acquire long-term safety data in children since they tend not to remain on the same therapy for an extended period of time. The general opinion was that a registry for adult RA is not really needed at this time for post-marketing surveillance.

Several issues must be considered before industry is willing to make an investment in the types of repositories discussed.

• Industry would want to be involved in the initial planning for collection of patient data.
• There must be a commitment to provide a certain amount of high-quality data over a specific time period.
• The data must be available for real-time analysis.
• The databases must be accessible and have the ability to communicate across datasets.
• There must be methods to explore the databases to look for other connections.

The discussion yielded many areas of interest for moving forward to increase the collaboration and partnering between industry, academia, and the government. NIAMS will consider these opportunities as we plan initiatives and continue discussions in the future.

Participants

BAKER, Daniel G., M.D. — Janssen Research and Development
BRIDGES, S. Louis, M.D., Ph.D. — University of Alabama at Birmingham
CURRAN, Mark E., Ph.D. — Janssen Research and Development
CURTIS, Sean P., M.D. — Merck Research Laboratories
CUSS, Francis M., M.B., B.Chir. — Bristol-Myers Squibb
DAVIS, John C., Jr., M.D., M.P.H — Genentech
FRANK, Lori, Ph.D. — Patient-Centered Outcomes Research Institute (PCORI)
GREGERSEN, Peter K., M.D. — Feinstein Institute for Medical Research, North Shore LIJ Health System
KOTZIN, Brian, M.D.— Amgen, Inc.
MCKEE, Charlotte, M.D. — Infinity Pharmaceuticals, Inc.
SCHANBERG, Laura, M.D. — Duke University Medical Center
WOODCOCK, Janet, M.D. (Co-Chair) — Center for Drug Evaluation and Research, Food and Drug Administration
YOO, Stephen, M.D. — MedImmune

NIAMS Staff

BUSCHMAN, Justine, M.S.
CARTER, Robert H., M.D.
KATZ, Stephen I., M.D., Ph.D. (Co-Chair)
KESTER, Mary Beth, M.S.
LINDE, Anita M., M.P.P.
MAO, Su-Yau, Ph.D.
McGOWAN, Joan A., Ph.D.
MOEN, Laura K., Ph.D.
SERRATE-SZTEIN, Susana A., M.D.
WANG, Yan, M.D., Ph.D.
ZIELINSKI, David, Ph.D.