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Meeting Reports 2004
Lupus Federal Working Group: Meeting Notes
June 22, 2004 (historical)
In FY 2003, Congress included language in the Labor-HHS appropriations bill that encouraged the Department of Health and Human Services (HHS) to establish a Federal Working Group on Lupus (FWGL). It is comprised of representatives from all relevant HHS agencies and any other government agency having an interest in lupus. These agencies exchange information on new developments and take advantage of new scientific opportunities in the field of lupus research.
Background and Introduction
The Lupus Federal Working Group (LFWG) met from 10:00 a.m. to 12:00 noon on June 22, 2004, in Bethesda, MD, at the offices of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH). Stephen I. Katz, M.D., Ph.D., Chair of the LFWG and Director of NIAMS, welcomed attendees to the second meeting of the LFWG. He emphasized the important role of the LFWG in keeping member organizations apprised in the area of research, to maximize collaboration and synergy. This type of information exchange and collaboration is already occurring, not only among the various Institutes within NIH, but also across different voluntary organizations that are a part of LFWG. Susana Serrate-Sztein, M.D., Co-Chair of the LFWG and Chief of the Rheumatic Diseases Branch of NIAMS, added her welcome and thanks to attendees. She reviewed the agenda, which emphasized contact with patients, a critical concern to advocacy organizations. The agenda included:
Research trials in bone marrow stem cell transplantation.
Dr. Serrate-Sztein noted the launch for two protocol trials, and that she would like LFWG members to be familiar with the protocol descriptions, the expectations, the obstacles during their development, and the ramifications of those obstacles.
- The SLE Biomarkers Working Group.
The SLE Biomarkers Working Group is engaged in a significant effort to identify and test biomarkers. Dr. Serrate-Sztein wanted to debrief LFWG members on the activities of this group.
- News and activities of interest.
The meeting included time for participants to report on their organizations' current activities and future plans.
Topic #1: Research Trials in Bone Marrow Stem Cell Transplantation
National Cancer Institute Protocol: Presentation Overview
Peter E. Lipsky, M.D., Scientific Director at NIAMS, introduced the meeting's first speaker, Steven Pavletic, M.D., Staff Clinician at the National Cancer Institute. Dr. Pavletic presented detailed information on a recently released protocol for hematopoietic stem cell transplantation (HSCT) for systemic lupus erythematosus (SLE). He began with background data on the burden of SLE and the use of allogeneic and autologous transplants for treatment. In 2001 SLE was responsible for 123,864 hospitalizations and 3,092 in-hospital deaths, which impacted Blacks more heavily than Whites or Hispanics. In 2002, 10,500 autologous transplants (virtually all stem cell transplants for nonmalignant diseases (e.g., anemia) are autologous) and 7,200 allogeneic transplants were conducted. Nonmalignant diseases such as SLE represent a very small percentage of this total.
The theory behind the use of allogeneic HSCT in autoimmune disease is that it can potentially have a positive impact on eradicating memory cells, acquiring tolerance, re-setting of the disease to an earlier stage, replacing the immune system, and creating graft-versus autoimmunity. Autologous HSCT may provide some of these benefits. A recently submitted study found that there was a 67% rate of sustained response, a 29% rate of transient response, and a 4% rate of no response among 51 cases of autologous HSCT in SLE patients. Based on these HSCT results, Dr. Pavletic believes that the use of autologous HSCT in severe SLE patients using high-dose cytoxan-based regimens is a promising approach--it appears to be effective, relatively safe (with total-related mortality of less than 10%), and durable (with responses that last up to four years). However, relapses do occur (approximately 25% of the time) and the trials to date have been poorly standardized and controlled. In addition, the response mechanisms are unknown while cures are uncertain. In short, there is a need to better understand the pathogenesis and pathophysiology of SLE and the HSCT treatment.
The new protocol (NIH protocol 04-C-0095: A Pilot Study of Intensified Lymphodepletion Followed by Autologous Hematopoietic Stem Cell Transplantation in Patients With Severe Systemic Lupus Erythematosus) is an attempt to develop a highly effective but less toxic treatment. Guiding principles behind the protocol are as follows:
- Lymphoselective (i.e., focused on the lymphoid system
without excessive toxic side effects).
- Strictly defined in terms of inclusion criteria, efficacy
endpoints, and definitions of flare and success.
To be eligible, patients must be between the ages of 15 and 40, fulfill American College of Rheumatology (ACR) criteria for SLE, have acceptable organ function, and have any of four types of active, treatment-resistant SLE (kidney, central nervous system, lungs, or anemia/thrombocytopenia). The primary efficacy endpoint is complete clinical response at 24 months post-transplant, maintained for at least 3 months. Complete response is defined as complete response in the target organ, no signs of active lupus (SLEDAI less than or equal to 3), and use of 10 grams or less of prednisone at 6 months and 5 grams or less at 12 months or later.
- Based on existing studies and knowledge of biology.
Dr. Pavletic believes that this approach is an improvement because the combination of agents is expected to be superior in efficacy to high-dose cyclophosphamide without added toxicity. He hopes that this protocol can serve as a foundation for cellular immunotherapy (including both autologous and allogeneic approaches) for autoimmune diseases, with the ultimate goal being to treat or cure disease and to improve immune reconstitution. To facilitate that goal, many patients’ blood samples are being studied to examine immune function and the effects of therapies on patients with normal and autoreactive responses.
The following key points came out of the discussion that followed Dr. Pavletic's presentation:
- No patients have been enrolled in the trial. Recruitment remains a challenge,
although a number of potential candidates have been identified. Several
candidates chose not to enroll for personal reasons. The protocol's sponsors
are engaged in a variety of activities to inform the public and physicians
about the protocol, including working through patient advocacy organizations.
- There was some concern that use of fludarabine during the conditioning
phase could cause pulmonary toxicity in patients with pulmonary disease.
Dr. Pavletic noted that fludarabine is not often used in patients with
autoimmune diseases, but has been used frequently in hematology/oncology
patients, including older individuals, without pulmonary toxicity side
effects. Immunosuppression is the main effect. In the protocol, fludarabine
is used in combination with cyclophosphamide; this combination can cause
cardiac toxicity in some patients.
- While the cutoff for evaluating patient benefits is 2 years, patients
will be followed for 5 years.
- To ensure safety, participating patients will be hospitalized for 3
weeks, which includes the conditioning and recovery stages. Patients would
not normally need to be hospitalized for this long.
- Participating patients must have failed standard cytoxan therapy for
severe SLE for 3 to 6 months depending on the type of SLE present, but
cannot have organ dysfunction or otherwise be critically ill. If they are
too sick, they will not respond well to the treatment protocol.
- No control group is planned. The comparison will be a "before" and "after" analysis
of the patient's condition. A randomized controlled trial may be conducted
once there is an opportunity to improve the protocol.
- Information on the trial is being distributed through print materials, on relevant web sites, and through patient advocacy organizations. An article on the protocol recently appeared in Lupus Now magazine.
NIAID Protocol: Presentation Overview
Ellen Goldmuntz, M.D., Medical Officer in the Division of Allergy, Immunology and Transplantation of the National Institute of, Allergies and Infectious Diseases (NIAID, an NIH Institute), presented an overview of a stem cell transplant, specifically a NIAID-sponsored protocol that is currently under development. Based on a Phase I trial conducted at Northwestern University in Chicago, IL, this new protocol will be tested in a Phase II trial that will compare the use of stem cell transplantation to currently available therapies for SLE. The primary objective is to test the safety of this approach; as a result, measures such as overall and transplant-related mortality, infection rates, and rates of engraftment will be analyzed. Because the focus is on the long term, the trial will not be stopped unless mortality rates are 10% or higher at the 6-month mark. The trial will also focus on the long-term efficacy of the stem cell transplant approach, with a Phase III trial planned for the future. Because the goal is to achieve a durable response to treatment, efficacy endpoints include: independence from all SLE drugs other than low-dose prednisone, quality-of-life indicators, disease/system assessments, and neuropsychiatric measures.
The goal is to enroll 100 patients who will be randomly assigned to the intervention group or the regular-care group. Participants will be treated in six transplant sites around the country, supported by a network of 20 "feeder" sites (large rheumatology practices housed at academic medical centers). Feeder sites were chosen so that they might enroll participants from across socioeconomic classes and racial and ethnic groups. Participants in the intervention group will undergo the transplant at one of the six sites, and then go home for follow-up care at one of the supporting rheumatology centers. Participants will make annual follow-up visits to the transplant center.
The intervention group will receive a nonmyeloablative conditioning regimen that includes treatment with cyclophosphamide and ATG followed by the stem cell transplant. The control group will receive any of a variety of "real-world" treatments for SLE, administered by rheumatologists at the feeder sites. The treatment for the control group was difficult and time-consuming to define. The ultimate decision, made by a panel of rheumatology experts, was for the control group to receive treatments based on current medical practice. Because there are little good data today on the efficacy of current practice, this trial may provide important information on the efficacy of current approaches (along with data on the risks and benefits of stem cell transplants).
The trial will follow participants for 5 years, with most key efficacy measures evaluated at 30 months. To be eligible for the trial, patients must be between the ages of 16 and 60 and meet the ACR criteria for SLE. They must be steroid-dependent and have no systemic end-organ damage or other organ problems that could significantly increase the chance of complications or death (e.g., cardiac disease, pulmonary disease). Participants must have failed standard therapy for 3 months.
Dr. Goldmuntz noted that the developers of this protocol are facing and/or will face a number of challenges, including how to keep patients engaged for the 5-year duration, how to educate physicians about stem cell transplantation (many are "afraid" of it), how to explain to patients assigned to the control group why they cannot receive stem cell transplants (many patients want the treatment), and how to satisfy FDA requirements related to the trial (e.g., ensuring comparability of care across sites).
The following key points came out of the discussion that followed Dr. Goldmuntz's presentation:
- Academic-based rheumatology centers are being used to ensure greater
consistency in care delivery for the intervention and control group. The
transplant centers can provide "back-up" assistance to these
centers if needed. Selection of the six transplant centers has not yet
- Third-party payers covered some of the costs of the Phase I trial. Since
NIH cannot communicate directly with third-party payers, the individual
centers will have to initiate discussions about coverage of the Phase II
trials. Under the contract that Blue Cross/Blue Shield (BC/BS) has with
the Federal Government to cover Federal employees, BC/BS will provide coverage
for NIAID-approved trials that are designated as being "pivotal" studies.
It is not clear whether BC/BS will provide financial support for smaller
phase II studies supported by NIAID, including those related to SLE. Other
insurers may follow BC/BS's lead on coverage.
- Both protocols (the NIAID protocol and the protocol described earlier by Dr. Pavletic) are "competing" for the same patients. While the regimens are different, the target patient populations are quite similar. In fact, the same individuals may well be offered participation in both trials, and thus have to decide which (if any) to enter. The goal will be to develop educational approaches that can help patients understand these and other trials so that they can make informed decisions. (The topic of patient education about trials may be appropriate for future LFWG meetings.) The NIAID trial may face more recruitment difficulties, since many would-be participants who are interested in stem-cell transplantation may not want to risk being assigned to the control group.
The FDA Role in These Protocols: Presentation Overview
Jeffrey N. Siegel, M.D., Team Leader of the Immunology and Infectious Diseases Team in the Division of Biological Internal Medicine Products at the Center for Drug Evaluation and Research within the Food and Drug Administration (FDA), described the FDA's perspective and role with respect to stem cell transplantation trials for SLE. Dr. Siegel spoke on behalf of Cynthia A. Rask, M.D., Director of the Office of Cell and Gene Therapy within the FDA, who could not attend the meeting. Dr. Siegel's team previously had responsibility for stem cell therapies for autoimmune diseases, including SLE. Several years ago, however, that responsibility shifted to the Office of Cell and Gene Therapy.
Dr. Siegel noted that many if not all of the "products" involved in stem cell transplantation have already been approved by the FDA. In fact, all of the drugs and biological agents used in the two protocols have been approved for various indications, although few have been approved specifically for treatment of SLE. Thus, the real "product" being evaluated by the FDA is the use of autologous stem cells in SLE patients. The FDA will evaluate all aspects of the protocol (e.g., mobilization, stem cell collection, conditioning, stem cell infusion, recovery) to make sure that the approach is reasonable and that there is an acceptable cost-benefit outcome. The overall goal is to facilitate new therapies that can meet previously unmet patient needs.
The activities of the FDA can vary depending upon the type of trial being conducted; it may be different for a pilot study of a new therapy, such as the NCI trial, than it is for an efficacy study with a control group, such as the NIAID trial. The primary focus of the FDA in either trial will be patient safety. Safety concerns will arise if mortality rates for stem cell transplantation for SLE are as high as the rates commonly seen for treatment of certain malignancies. To minimize the chances that this could occur, FDA focuses on ensuring that careful attention is paid to choosing appropriate patient populations and to other safeguards that can minimize risks to patients. Another critical role for FDA is to be a central point for communicating any patient safety concerns that arise during the trials. In fact, organizations are required by law to report such concerns, so that FDA can then disseminate these concerns to all relevant parties, thus ensuring that as few patients as possible are harmed. In Phase II and III trials that include a control group (i.e., those designed to establish efficacy), FDA will also look for rigid definitions of success (e.g., no toxicity, little use of immunosuppressive drugs). Dr. Siegel also noted that pharmaceutical companies are usually involved in approaching FDA for approval. In the case of stem cell transplantation (where no new drugs are involved), it is less clear what organization(s) will take the lead in seeing this through to approval.
The following key points came out of the discussion following Dr. Siegel's remarks:
- Dr. Siegel is not sure who within Dr. Rask's office (i.e., which clinical
reviewer) will be assigned to stem cell transplant trials or will be receiving
any safety concerns that might arise out of such trials.
- The latest discussions suggest that FDA will not be approving the entire
regimen contained within the NCI or NIAID protocols, nor the individual
steps included in the different phases (e.g.. the use of specific drugs).
Rather, it will be approving the use of autologous stem cells. The product
label, however, would specify the exact regimen in the protocol, and individual
centers would need to be licensed to give the regimen.
Topic #2: SLE Biomarkers Working Group
Barbara Mittleman, M.D., Director of the Office of Scientific Interchange at NIAMS, reviewed the history, current status, and future plans of the SLE Biomarkers Working Group. The group formed in response to a need for SLE biomarkers to assist with diagnosis, prognosis, assessment of disease activity and disease-related damage, and response to treatment. This coordinated effort to develop biomarkers for SLE is thought to be important for several reasons: First, SLE is a heterogeneous disorder that follows a "waxing and waning" course with variable outcomes. Second, there are few validated instruments to assess the disease, and little consensus on such instruments. Finally, reaching consensus on the development of SLE biomarkers has proved to be a tremendous challenge for all parties involved.
The SLE Biomarkers Working Group's roots go back to an FDA meeting of experts held in April 2003. At this meeting a draft guidance document was developed in collaboration with a broad-based group of stakeholders that included patient advocacy groups and pharmaceutical companies. Several additional planning meetings were held in late 2003 and early 2004. These meetings, which included representatives from NIH, FDA, advocacy organizations, the pharmaceutical industry, and other organizations, addressed issues such as: whether and how the various groups could work together effectively; what approaches could be used to identify and validate biomarkers for SLE; and what data and infrastructure would be required for the effort. A Steering Committee for the Working Group was elected in February 2004, and this committee met in May 2004 at the International Lupus meeting. In June 2004, the Steering Committee developed a planning grant proposal to conduct a clinical trial to evaluate the first 5 identified SLE markers.
Dr. Mittleman noted that although the idea for the Working Group initially came out of the Intramural Research Program within NIAMS, the Working Group today has an independent existence and is run by a community of stakeholders. The principles for the group are inclusivity (anyone who wants to participate can do so), transparency (proceedings of all meetings are available), scientific and clinical utility, practicality, and collaboration. The group consists of four committees: the Biomarker Identification Committee, the Biomarker Validation Committee, the Sample and Data Collection Committee, and the Infrastructure Committee. Scientist-clinicians are on each committee, and each is also supported by the overall Steering Committee and the Scientific Advisory Board.
Topic #3: News and Activities of Interest
The meeting concluded with attendees reporting on current activities within their organizations:
- Jane E. Salmon, M.D., Research Chair of the ACR noted that ACR is actively
participating in the two protocols/trials that were discussed. Dr. Salmon
is also the Chair of the Infrastructure Committee of the SLE Biomarkers
Working Group. ACR's national meeting in the fall will feature educational
programs and opportunities for subgroups (e.g., investigators) to convene.
ACR is also working collaboratively with the Lupus Foundation of America
(LFA) to revise the criteria related to diagnosing lupus.
- Barbara E. Boyts, President of the Alliance for Lupus Research (ALR)
emphasized her organization's excitement and support for the various activities
discussed at the meeting. ALR is focused exclusively on lupus research,
and currently has a grants application outstanding, with applications due
on September 1, 2004 (last year, $6.7 million was awarded to 8 new investigators).
Ms. Boyts is also involved in the SLE Biomarkers Working Group as a member
of a committee looking at infrastructure issues.
- Margaret G. Dowd, President of the Lupus Research Institute (LRI), highlighted
her organization's support of new science and therapies, especially those
where the data are not sufficient to allow for initial NIH funding. Since
2000, LRI has funded 50 lupus-related studies, 42 of which are still in
process. 73 percent of investigators from the first round of those studies
have approached NIH about additional funding. An initial investment of
$2.5 million by LRI has led to much higher levels of funding from NIH,
suggesting that LRI is supporting important scientific breakthroughs. LRI
recently announced a $3 million commitment to support a new round of clinical
investigations. Six of the 13 grants relate to new treatments for SLE,
and the remaining seven have been given to younger investigators, often
at the assistant professor level. LRI is also supporting 14 fellows, a
testimony to the organization's financial commitment to new SLE researchers.
Finally, LRI is opening a new SLE foundation that will focus on racial
disparities found in SLE. The foundation plans to conduct outreach in inner
cities (e.g., Chicago, New York) to find SLE cases, and Ms. Dowd suggested
that workforce issues related to SLE (i.e., attracting new people to the
field and retaining them) be considered as an agenda item at a future LFWG
- Mary Waterman, M.P.H, of the Arthritis Foundation (AF), noted that the
AF has supported more than 80 grants related to lupus, with 21 of these
being through its partnership with ALR. Total financial commitments from
AF have been approximately $17 million.
- Sandra C. Raymond, President and CEO of the Lupus Foundation of America
(LFA) highlighted her organization's emphasis on lupus research and education.
Within the area of research, LFA has three main interests: biomarker validation,
working with the ACR to revise the criteria related to the diagnosis of
lupus, and working with the Centers for Disease Control and Prevention
(CDC) to support research related to the epidemiology of lupus.
- Reem Ghandour, M.D., of the Office of Women's Health (OWH) within the
Health Resources Services Administration (HRSA), noted that, pending final
approval, HRSA OWH will fund lupus training for primary care providers
along the U.S.-Mexico border region. HRSA is also providing funding to
community-based centers to implement patient education and awareness programs
related to lupus.
- Katherine Snider, President of Rheuminations, Inc., noted that her organization
is a private foundation that provides individual grants to leaders in the
area of lupus research. The foundation is supporting the Lupus Research
Center within the Hospital for Special Surgery in New York. Rheuminations
is also working to enhance education and awareness of lupus, and has provided
seed money to the Lupus Clinical Trials Consortium, a group of 27 centers
in the U.S. and Canada. This money is supporting the development of infrastructure
that will allow for therapeutic trials in the area of lupus.
- Charles Helmick, M.D., Medical Epidemiologist in the Arthritis Program at the Centers for Disease Control and Prevention (CDC) noted that his agency is working to develop lupus statistics and descriptive epidemiological studies. He suggested discussing patient registries at a future meeting.
Dr. Serrate-Sztein adjourned the meeting by thanking attendees for coming, and encouraging them to contact her with new information, questions, or suggestions about topics for future LFWG meetings.