The purpose of this announcement is two-fold: first, to inform potentially interested individuals, institutions and organizations of a draft project requirement of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), designed to establish a Collaborative Network for Clinical Research on Immune Tolerance, and second, to solicit comments from interested parties with respect to the scope, design and requirements of this draft solicitation.
Please note that proposals are not being solicited at this time. With this announcement, the NIAID is soliciting comments and recommendations on the entire draft project requirement (i.e., Statement of Work, Technical Evaluation Criteria, and Reporting Requirements) in order to: (1) determine interest in this solicitation; (2) assure that requirements included in the documentation will meet the intent of the solicitation; and very importantly, (3) identify or clarify what may appear to be problems, conflicts, or obstacles for an institution or organization that might otherwise wish to become a potential offeror.
A major priority of the NIAID Division of Allergy, Immunology and Transplantation is the acceleration of research on immune tolerance, particularly the application of basic knowledge to the clinical setting. The potential impact on human health is great, encompassing a broad range of immune-mediated diseases, including: autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis; asthma and allergic diseases; and rejection of transplanted solid organs, cells and tissues. A solid experimental foundation already exists and many unique reagents are now available to support translational research and to pursue promising clinical applications.
The Collaborative Network for Clinical Research on Immune Tolerance solicitation will seek to fund a consortium of institutions and organizations with the scientific, clinical and technical expertise necessary to: (1) develop a long-term scientific agenda to accelerate research on immune tolerance for the treatment of multiple immune-mediated diseases; (2) design and conduct clinical trials at all phases to determine the safety, toxicity and efficacy of promising tolerogenic approaches; (3) design and conduct studies of the underlying mechanisms involved in the induction, maintenance and loss of tolerance as an integral part of clinical trials sponsored by the Collaborative Network, as well as by other Federal and private organizations and companies; and (4) conduct research to develop and validate assays for measuring the induction, maintenance and loss of tolerance in humans.
The Collaborative Network will be required to demonstrate proven expertise in basic immunology, translational research and clinical research, as well as the capacity to organize and manage a multidisciplinary, integrated research program. Furthermore, because the design and development path for the research to be carried out cannot be entirely anticipated, the Collaborative Network must have a clear vision of how new scientific findings and new tolerogenic approaches will be integrated into the scientific agenda.
The Juvenile Diabetes Foundation International (JDFI) is cosponsoring this research program. The JDFI's mission is to fund research aimed at curing type 1 diabetes and its complications. The Foundation is the largest non-governmental supported of diabetes research. By joining the NIAID in sponsoring the Collaborative Network, the JDFI seeks to accelerate the application of tolerogenic approaches in the clinical setting.
The Request for Proposals will detail four (4) different components, each with its own work statement. Part A provides for the establishment of the Collaborative Network and for clinical trials and mechanistic studies in kidney and islet transplantation. Part B encompasses research to develop and validate assays to measure the induction, maintenance and loss of tolerance in humans. Part C expands the scope of the Collaborative Network to incorporate clinical trials and mechanistic studies in asthma and allergic diseases. Part D expands further the scope of the Collaborative Network to incorporate clinical trials and mechanistic studies in autoimmunity.
The NIAID intends to review proposals and award one cost-reimbursement contract where competing offerors will be evaluated for:
Once awarded, the progress of the Collaborative Network will be determined by advancements in the design and implementation of the research to be carried out. An external advisory committee will assist NIAID staff in overseeing the Network's progress.
As provided for by FAR.5.205 entitled "Special Situations," a draft project requirement is being broadcast.
We encourage you to respond to Rosemary Hamill, NIAID Contracting Officer, on this matter, using the Response Guidelines provided at the end of the Announcement, to indicate issues or elements you are particularly in favor of, or which you find problematic to the response capacity of your institution or organization. We are particularly interested in knowing what issues are paramount in your decision-making process concerning this solicitation, and if, after consideration, a "no" decision is reached, why your organization is unable or chooses not to respond to this solicitation. Please be as direct as possible.
This research program will require extensive collaboration among investigators from a variety of disciplines, many of whom may not have worked together previously. To assist individuals, institutions and companies in developing collaborations necessary for responding to the solicitation, the NIAID has established a separate Interested Parties Web Site. This web site is a searchable database of Listings posted by individuals interested in participating in this research program; it is not a chat room for the exchange of information among listed parties. A Listing on this web site includes name, institution, contact information, and areas of interest within the solicitation, expertise, and comments concerning expertise. These listings are searchable by various parameters, including: name; institution; areas of interest included in the solicitation; and expertise. We encourage you to use this web site to indicate your interest in responding to this RFP, your area of scientific expertise, and most importantly, the specific components of the research to be carried out under this solicitation for which you and/or your institution are qualified. Posting of information at this web site indicates willingness to be contacted by other interested parties; however, listing does not commit one to participate and offerors may submit proposals without being listed as an interested party.
This web site will remain open and accessible to interested parties until approximately May 1, 1999.
Please do not use the Interested Parties Web Site to provide comments to the Government. Specific instructions on submitting comments to the Government are provided at the end of the Announcement, under Response Guidelines.
Introduction
Part A: Kidney and Islet Transplantation
Part B: Development and Validation of Tolerance Assays
Part C: Asthma and Allergic Diseases
Part D: Autoimmune Diseases
Deliverables and Reporting Requirements
Proposed Evaluation Criteria
Successful tolerance induction is a major therapeutic goal for the treatment of immune system diseases. The potential impact on human health is great, encompassing a broad range of immune-mediated diseases, including: autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis; asthma and allergic diseases; and graft rejection in kidney, pancreas, heart, lung, bone marrow and cell transplantation. Advances in tolerance induction will provide valuable new therapeutic strategies that do not require life-long, globally immunosuppressive therapy with its deleterious side effects, and the knowledge required to induce and maintain a tolerant state will also be important for preventing immune unresponsiveness in the development of vaccines for tumors and infectious diseases. A solid experimental foundation already exists and many unique reagents are now available to support translational research and to pursue promising clinical applications.
Accelerating research on immune tolerance is a major priority of the Division of Allergy, Immunology and Transplantation of the National Institute of Allergy and Infectious Diseases (NIAID). As part of the Institute's recent efforts to move this field of investigation forward, a series of activities were initiated in the fall of 1997. A long-range, comprehensive research plan was developed. In February 1998, this plan was reviewed by a panel of experts in basic and clinical immunology from academia and industry with strong endorsement for the overall approach, scope and timeliness of the plan. In April 1998, the NIAID convened a second expert panel to review ethical issues in the design, implementation and monitoring of clinical trials of transplant tolerance. Copies of the NIAID Plan for Research on Immune Tolerance, the Report of the NIAID Expert Panel on Immune Tolerance, and the Recommendations of the NIAID Expert Panel on Ethical Issues in Clinical Trials of Transplant Tolerance are located on the NIAID web site: http://www.niaid.nih.gov/research/dait.htm.
This solicitation to establish the Collaborative Network for Clinical Research on Immune Tolerance is a major program emanating from this recent scientific planning process, and seeks to fund a consortium of scientific and clinical investigators to: (1) develop a long-term scientific agenda for clinical trials and mechanistic studies; (2) design and conduct clinical trials at all phases to determine the safety, toxicity and efficacy of tolerogenic treatment strategies for multiple immune system diseases; and (3) design and conduct research to delineate the underlying mechanisms of immune tolerance as an integral part of the clinical trials undertaken by the Collaborative Network, as well as clinical trials sponsored by other Federal and private sector organizations and companies.
The Juvenile Diabetes Foundation International (JDFI) is cosponsoring this research program. The JDFI's mission is to fund research aimed at curing type 1 diabetes and its complications. The Foundation is the largest non-governmental supporter of diabetes research. By joining the NIAID in cosponsoring the Collaborative Network, the JDFI seeks to accelerate the application of tolerogenic approaches in the clinical setting.
It is anticipated that one (1) contract will be awarded to a consortium of institutions comprising the Collaborative Network for a period of seven (7) years.
This Request for Proposals (RFP) details four (4) different components, each with its own work statement.
Part A solicits proposals for clinical trials and mechanistic studies in kidney and islet transplantation.
Parts B, C, and D describe Task Orders that may be issued by the Government.
Kidney Transplantation
Transplantation is now routine therapy for end-stage renal disease, with one-year graft survival approaching 90% using standard immunosuppressive therapy. However, long-term graft survival has not improved appreciably since the early 1980s and only about 45% of cadaveric kidneys survive ten years post-transplant. For other organs, (e.g., liver, lung and pancreas), long-term graft survival does not approach this level. While new immunosuppressive drugs have reduced acute rejection in the first year post-transplant, it is clear that these therapeutic improvements have not significantly altered long-term clinical outcomes. Therefore, much recent attention has focused on the potential for the induction of donor-specific immune tolerance to achieve long-term graft survival, abrogating the need for non-specific, life-long immunosuppressive therapy with its deleterious and often life-threatening side effects. Although certain promising tolerogenic molecules are being tested in humans for the treatment of selected autoimmune diseases, and have been shown to induce donor-specific tolerance in rodent and non-human primate transplant models, these approaches have not been evaluated for transplantation in humans.
The clinical application of tolerance induction approaches in kidney transplantation will require: (1) the design and evaluation of different treatment regimens, e.g., monotherapy, combination therapy of tolerogenic reagents with selected standard immunosuppressive drugs, co-administration of donor marrow cells with tolerogenic reagents at the time of transplant, etc.; (2) assessments of the safety and efficacy of different dosages and pre-treatment, maintenance and retreatment strategies; and (3) integrated studies to delineate the underlying mechanisms of tolerance induction strategies.
Islet Transplantation
Islet transplantation seeks to restore pancreatic beta cell function by replacing the pancreatic insulin-producing cells destroyed by immune-mediated injury in type 1 diabetes mellitus. The ultimate goal is to provide a sufficient number of functioning islets to achieve normal insulin production and secretion, thereby preventing the serious renal, neurologic and vascular complications of this disease of in-patients with type 1 diabetes mellitus, fewer than 5% of those receiving islet transplants in conjunction with aggressive immunosuppressive therapy remain insulin-independent at one year. This poor outcome could be the result of recurring autoimmune destruction and/or immune rejection. Furthermore, the immunosuppressive agents themselves are responsible for at least some of this destruction. These sobering results highlight the importance of developing other approaches to ensure successful engraftment, survival and normal function. Moreover, islet transplantation is an exceptional clinical setting to test tolerance induction protocols since transplant failure is not life-threatening (as in heart or liver transplantation), and patients can be returned to insulin therapy. In addition, clinical research in islet transplantation will provide valuable new information on the ability to induce tolerance in the context of an underlying autoimmune disease, including abrogating the underlying disease.
Most research in islet transplantation is being conducted in rodent models, with some promising studies in non-human primates, and a small but evolving effort in humans. The immunologic hurdles are considerable and some of the major areas in need of further investigation in terms of the impact on tolerance induction include: (1) identification of various transplant sites, modes of islet delivery, and number of islets required to optimize engraftment and short- and long-term survival; (2) evaluation of specific treatment regimens including pre-treatment, maintenance and retreatment regimens; (3) identification of the immunological mechanisms of early cell destruction and therapeutic interventions to prevent such destruction; (4) further development of approaches to improve short- and long-term survival by combining islet transplantation with promising tolerogenic molecules and reagents; (5) delineation of the role of disease recurrence in the destruction of transplanted islets; and (6) the development of "super" islets, including genetically engineered beta cells and tissues, to improve engraftment and to escape autoimmune injury and rejection.
Part A of this solicitation seeks to establish the Collaborative Network for Clinical Research on Immune Tolerance as a major program emanating from NIAID's recent scientific planning process, and to fund a consortium of scientific and clinical investigators to: (1) develop a scientific agenda focused on immune tolerance for kidney and islet transplantation; (2) design and conduct clinical trials at all phases to determine the safety, toxicity and efficacy of tolerogenic treatment strategies to improve graft survival; and (3) design and conduct research to delineate the underlying mechanisms of the induction, maintenance and loss of immune tolerance as an integral part of the clinical trials undertaken by the Collaborative Network as well as clinical trials sponsored by other Federal and private sector organizations and companies.
Additional Information on the Scope and Requirements of Part A of This Solicitation
Work Statement
Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities not otherwise provided by the Government under the terms of this contract, as needed to perform the work set forth below.
Specifically, the Contractor shall:
The Network shall include clinical expertise in kidney transplantation, islet transplantation, asthma and allergic diseases, and autoimmune diseases.
a) A discussion of the state-of-the-art of research focused on elucidating the underlying mechanisms of immune tolerance and on evaluating tolerogenic approaches in rodent, non-human primate and human studies.
b) A description of knowledge gaps and scientific opportunities relevant for the clinical application of tolerogenic approaches to human studies in kidney and islet transplantation.
c) A plan to accelerate research on immune tolerance in humans, including:
(1) A conceptual framework delineating approaches to tolerance induction to improve graft survival in human kidney and islet transplantation, priorities among various approaches and the rationale for such priorities, including potentially promising reagents and molecules in development;
(2) The relevance of each approach to human kidney and islet transplantation;
(3) A conceptual framework for delineating underlying mechanisms of tolerogenic approaches through studies conducted as an integral part of the clinical trials in kidney and islet transplantation;
(4) A description of promising clinical trials of tolerance induction in kidney and islet transplantation, including the rationale for the selection of tolerogenic approaches, overall study design and patient populations; and
(5) A description of promising mechanistic studies to be incorporated as an integral part of the clinical trials in kidney and islet transplantation, including the rationale for the selection of the mechanistic studies, proposed techniques, and the overall design of such studies.
[NOTE #1 TO OFFEROR: A proposed scientific agenda shall be submitted as part of the Technical Proposal. The Government anticipates that a succinct scientific agenda of approximately 5–10 pages in length will be adequate to address this requirement. In addition, since the design and development path for the research to be carried out under Part A of this solicitation cannot be entirely anticipated, Offerors are not expected to include in the Technical Proposal sample protocols or detailed research designs for mechanistic studies.]
[NOTE #2 TO OFFEROR: The Technical Proposal shall include a brief description of the plan for the scientific management and coordination of the Network. The Government recognizes that the specific processes and criteria to be used by the Network to manage, coordinate, establish priorities, and redirect scientific and fiscal resources will be developed fully after award of the contract. Therefore, it is anticipated that the plan for the scientific management and coordination of the Network, to be submitted as part of the Technical Proposal, can be adequately addressed in approximately 5–8 pages. All such plans, procedures and policies will be subject to review and approval by the Government.]
[NOTE #3 TO OFFEROR: For cost estimating purposes, Offerors shall assume that approximately 30% of the total costs of the contract will be required for clinical trials, exclusive of personnel costs. However, the actual costs required for the conduct of clinical trials will depend on multiple factors, including: the phase of the clinical trials to be conducted; the number of patients required; the study population; the mechanistic studies and type and number of samples required, etc. In addition, Offerors shall include in the Technical Proposal a plan for the recruitment and retention of study participants.]
[NOTE #4 TO OFFEROR: For cost estimating purposes, offerors shall assume that approximately 20% of the total contract costs will be required for mechanistic studies, exclusive of personnel costs.]
[NOTE #5 TO OFFEROR: The Technical Proposal shall include documentation on the qualifications, knowledge, experience, education, competence, availability and decision-making skills and authority of: (1) the Project Director, (2) scientists proposed to carry out mechanistic studies, (3) clinical investigators proposed to carry out clinical trials; and (4) technical and administrative staff. Documentation shall also include all previous and current projects of a similar nature, including the grant or contract number, the sponsoring agency, the project officer, and description of the project. Curricula Vitae of all proposed personnel shall be included in the proposal. In addition, the Offeror shall describe the responsibilities and level of effort of all proposed personnel who will be assigned to the contract, including subcontractors, as well as an administrative framework indicating clear lines of authority. All costs associated with proposed personnel shall be provided in the Business Proposal.]
[NOTE #6 TO OFFEROR: The Government will provide salary support for the scientific, clinical, technical and administrative personnel. For cost estimating purposes, Offerors shall assume that approximately 50% of the total contract costs will be required for personnel support, including all scientific, clinical, technical and administrative personnel assigned to the contract. In addition, Offerors may propose the establishment of shared resources and facilities to provide the Network with access to critical scientific and technical support services in a cost-effective manner. For purposes of this solicitation, these resources are referred to as "core resources." The Technical Proposal shall describe the services to be provided by each proposed core resource and shall discuss the rationale for these services. All costs associated with proposed core resources shall be provided in the Business Proposal.]
[NOTE #7 TO OFFEROR: Offerors shall include in the Technical Proposal a proposed organization for the governance of the Network, including the composition of the Executive Committee. All concepts, clinical protocols, detailed designs for mechanistic studies, Network policies and procedures will be reviewed and approved by the NIAID. This NIAID review process may involve participation by investigators not supported by the Network.]
[NOTE #8 TO OFFEROR: Travel, lodging and meal costs associated with these meetings will be provided from non-Network sources. Therefore, no travel costs for these purposes shall be included in the Business Proposal.]
[NOTE #9 TO OFFEROR: The NIAID will establish an Advisory Committee to review all NIAID-supported research programs focusing on immune tolerance. This committee will meet at least once each year and provide advice to NIAID on current and future directions to accelerate progress in this area. The travel costs associated with the participation of Executive Committee members in this annual meeting will be provided from non-Network sources. Therefore, no travel costs for these purposes shall be included in the Business Proposal.]
Offerors submitting a proposal under this solicitation must prepare a proposal that includes the required work outlined in Part A AND the required work outlined below in the Task Orders for Parts B, C and D. Proposals for Part A alone or Parts B, C and D alone will not be accepted for review or considered for award. Offerors shall not submit a Business Proposal at this time for the Task Order activities specified in Parts B, C and D of this solicitation.
Issuance of Task Orders for Parts B, C and D will be solely at the discretion of the Government and will be based on technical merit, need, and the availability of funds during the seven-year period of performance. If the Government decides to issue a Task Order, the Contractor will be provided with a detailed work statement. At that time, the Contractor shall submit a complete Technical Proposal addressing the requirements set forth in the Task Order work statement, as well as a Business Proposal, for review and evaluation by the Government. The technical merit of all such proposals will be reviewed by NIAID staff and selected members of the NIAID Advisory Committee for Research on Immune Tolerance. Task Order activities will be accomplished on a cost reimbursement basis.
Research leading to the development of improved treatments for autoimmune diseases, asthma and allergic diseases and transplant rejection is a major component of the mission of NIAID's Division of Allergy, Immunology and Transplantation. The Task Order activities specified below for Part B of this solicitation will expand the scope of the Network to include development of standardized assays and reliable markers of immune tolerance in kidney and islet transplantation, autoimmune diseases and/or asthma and allergic diseases.
The current lack of validated markers of immune tolerance has significant implications for the rational design of tolerogenic treatment protocols and the appropriate monitoring of study participants. The development of immune/surrogate markers of in vivo tolerance in humans is critical to advancing the application of tolerance induction therapeutic regimens. Sensitive indicators and/or predictors of early induction or loss of tolerance will facilitate clinical trials by expanding the universe of informed treatment options, including re-treatment to induce tolerance or standard therapy.
The development of useful immune/surrogate markers involves complex issues surrounding the selection, validation, quantitation, standardization, and population application of tolerance "biomarkers", and the design of clinical protocols to control the four major sources of variability which may confound clinical application: biological diversity, sampling diversity, variability of detection procedures, and validation against acknowledged disease endpoints. In addition, putative immune/surrogate endpoints should be biologically plausible, measurable by standardized and reliable assays, represent early events in the causal pathway, and exhibit dose-responses. Perhaps most importantly, immune/surrogate markers should be capable of measuring the effect of the intervention on clinical outcome. The identification and validation of a biomarker as a valid immune/surrogate marker for tolerance is a stepwise process involving smaller "transitional" studies and larger second-generation trials in which both primary outcome and putative surrogates are measured. Transitional studies are used to move new markers from the laboratory into evaluation in humans, and are designed to address specific questions of assay validity, treatment/marker associations, marker/disease associations, and inter- and intra-individual variability. Promising markers need to be further developed and then tested in current and future clinical trials in transplantation, autoimmune disease and asthma and allergic disease to definitively address the issues of optimal representation, and to test the adequacy of markers to capture the effect of treatment on clinical outcome. Unfortunately, clinical studies frequently lack the statistical power to allow definitive conclusions about the value of potential immune/surrogate markers or are terminated before sufficient evidence can be accumulated. The choice of surrogate markers will differ by disease and by tolerogenic approach and additional research is needed to identify the most useful markers for monitoring the course of specific types of immune modulation and tolerance induction.
Work Statement
Independently, and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified personnel, materials, equipment and facilities, not otherwise provided by the Government under the terms of this contract, as needed to:
[NOTE #10 TO OFFEROR: The Technical Proposal shall include an overall plan to incorporate into the Network the activities delineated in this Task Order. The plan shall address the following components of this expansion of the Network's activities:
The Government anticipates that descriptions of approximately 5–7 pages in length will be adequate to address this requirement.]
Research leading to the development of improved treatments for asthma and allergic diseases is a major component of the mission of NIAID's Division of Allergy, Immunology and Transplantation. The activities specified in the Task Order for Part C of this solicitation will expand the scope of the Network to include: (1) clinical trials to evaluate the safety, toxicity and efficacy of tolerogenic approaches for the treatment of asthma and allergic diseases; and (2) studies of the underlying mechanisms involved in the induction, maintenance and loss of immune tolerance as an integral part of Network-sponsored clinical trials in asthma and allergic diseases, as well as clinical trials in this disease area sponsored by other Federal and private sector organizations and companies.
Asthma and allergic diseases are attractive models for the development of new approaches to alter the human immune response. These diseases are increasing in prevalence and account for high medical and social costs. Despite the availability of proven therapies and many new agents in development, even the most effective pharmacotherapies have serious limitations. Some data suggest that either reduced allergen exposure, or conventional allergen immunotherapy, can block the development and/or exacerbations of asthma. However, there are obstacles to translating these findings into clinical practice, perhaps because present approaches to environmental control do not sufficiently reduce allergen levels, and because conventional immunotherapy causes only weak modulation of the human immune response. The most promising approach is to develop new methods of inhibiting allergic immune responses and/or inducing tolerance to allergens.
The development of new approaches would be enhanced by the many widely available, well standardized and clinically validated tests, including blood studies, skin tests, and pulmonary function tests, that can be used to characterize allergic responses from the immunological and physiological perspectives. Moreover, it may soon be possible to enhance the identification and stratification of at-risk individuals based on the discovery of genes that predispose to asthma and atopy.
Allergen immunotherapy was developed empirically ~80 years ago, and relatively little effort has been made to develop more robust and long-lasting allergen immunotherapies, based on fundamental principles of immunology. However, concerns about the efficacy of conventional immunotherapy have stimulated research into new approaches to tolerize to allergen. A variety of avenues are being explored and build on the fact that many clinically important allergens have been identified, purified, cloned, epitope-mapped, produced as biologically active recombinant proteins, and administered safely by mucosal and cutaneous routes. With these reagents, the timing, dose, route, and molecular form for the allergen can be tightly controlled. Approaches that combine non-antigen-specific methods (e.g., second signal blockade and cytokine modulation) and antigen-specific tolerance induction regimens appear very promising in animal models and are close to entering Phase I and/or Phase II clinical studies in humans. Among these are: (1) "DNA vaccines" comprised of plasmid DNA encoding recombinant allergens, which induce long-lasting allergen-specific tolerance in mice; (2) immunostimulatory oligonucleotides, small sequences of bacterial DNA that drive the Th1 immune responses when co-administered with protein allergens; (3) T cell costimulatory blockade in conjunction with allergen challenge; (4) peptide vaccines representing T cell epitopes of allergen (5) immunization with Mycobacterium vaccae, which non-specifically drives Th1 immune responses; (6) monoclonal antibodies to IgE, which deplete plasma IgE and down-regulate mast cells and basophil receptors for IgE; and (7) co-administration of allergen and cytokines.
Independently, and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified personnel, materials, equipment and facilities, not otherwise provided by the Government under the terms of this contract, as needed to:
[NOTE #11 TO OFFEROR: The Technical Proposal shall include a plan to incorporate into the Network these Task Order activities. The plan shall address the following components of this expansion:
The Government anticipates that descriptions of approximately 5–7 pages in length will be adequate to address this requirement.]
Research leading to the development of improved treatments for autoimmune diseases is a major component of the mission of NIAID's Division of Allergy, Immunology and Transplantation. The activities specified in the Task Order for Part D of this solicitation will expand the scope of the Network to include: (1) clinical trials to evaluate the safety, toxicity and efficacy of tolerogenic approaches for the treatment of autoimmune diseases, and (2) studies of the underlying mechanisms involved in the induction, maintenance and loss of immune tolerance as an integral part of Network-sponsored clinical trials in autoimmunity, as well as clinical trials in this disease area sponsored by other Federal and private sector organizations and companies.
Efforts to induce tolerance in autoimmunity have focused primarily on the oral administration of antigens. Oral administration of both high and low dose antigen results in a phenomenon termed "oral tolerance" in which the immune response to subsequent systemic administration of antigen is blocked. Oral tolerance can be induced in animal models and is now being evaluated in human diseases. However, the encouraging responses in animal studies have not been duplicated in recent clinical trials of rheumatoid arthritis and multiple sclerosis. There are a number of promising tolerogenic approaches other than oral tolerance that can be pursued in immune-mediated diabetes and other autoimmune diseases. These include: costimulatory blockade; anti-cytokine monoclonal antibodies; hematopoietic stem cell and bone marrow transplantation; and gene transfer-based therapies for cytokine modulation. The rationale for pursuing clinical trials in autoimmunity is supported by promising pre-clinical studies as well as the availability of tolerogenic reagents and molecules.
Independently, and not as an agent of the Government, the Contractor shall furnish all necessary services, qualified personnel, materials, equipment and facilities, not otherwise provided by the Government under the terms of this contract, as needed to:
[NOTE #12 TO OFFEROR: The Technical Proposal shall include a plan to incorporate into the Network these Task Order activities. The plan shall address the following components of this expansion:
The Government anticipated that descriptions of approximately 5–7 pages in length will be adequate to address this topic.]
[NOTE #13 TO OFFEROR: Clinical trials and mechanistic studies of islet transplantation for the treatment of type 1 diabetes mellitus are provided for in the work statement for Part A of this solicitation. Therefore, the research being solicited in Part D will not include islet transplantation for type 1 diabetes mellitus. Mechanistic studies and clinical trials of tolerogenic approaches for the treatment of type 1 diabetes other than islet transplantation, as well as tolerogenic approaches for other autoimmune diseases, are within the scope of Part D of this solicitation.]
The Contractor is required to formally report progress through: (1) submission of an annual written technical report, (2) verbal and written materials presented at each of the Executive Committee meetings, to be held three times each year; and (3) verbal and written presentations at the annual review by NIAID's Advisory Committee for Research on Immune Tolerance, to be held in conjunction with one of the Executive Committee meetings.
Annual Technical Report
At the completion of each contract year, the Contractor shall submit four (4) copies of the Annual Technical Report as described below. One (1) copy shall be submitted to the Contracting Officer, and three (3) copies shall be submitted to the Project Officer. The Annual Technical Report shall be factual and concise and consist of the following:
A cover page containing:Contract number and title;
Period of performance being reported;
Contractor's name and address;
Author(s); and
Date of submissionSection I - The scientific agenda for the Collaborative Network and a brief description of any changes in scientific direction.
Section II - A section that outlines the status of all identified work tasks from the Statement of Work and provides a brief description of overall progress, including: (1) approved concepts for clinical trials and mechanistic studies; (2) clinical trials and mechanistic studies implemented, completed or terminated/curtailed; (3) pertinent interim and final data resulting from clinical trials and mechanistic studies; and (4) policies and procedures developed or revised for the overall management and coordination of the Network.
Section III - A brief description of all impediments in carrying out the work tasks, whether affecting performance or costs, and recommendations for their solution.
Section IV - A brief description of tasks to be completed during the next year and of any difficulties anticipated.
Executive Committee Meetings
The Contractor shall provide verbal progress reports, with any appropriate written documentation, at the meetings of the Executive Committee for the Network. This shall include: (1) status of approved concepts for clinical trials and mechanistic studies; (2) review of proposed concepts for clinical trials and mechanistic studies; (3) progress with respect to ongoing clinical trials and mechanistic studies; (4) interim and final results of clinical trials and mechanistic studies; and (5) proposed changes in scientific direction, including the reallocation of Network resources.
Annual Review by NIAID Advisory Committee for Research on Immune Tolerance
At the end of each contract year, the Project Director shall meet with the NIAID External Advisory Committee to report on the organization, management and scientific progress of the Collaborative Network, as well as new knowledge and scientific opportunities and their effect on the scientific agenda and research conducted by the Collaborative Network. Copies of the Annual Technical Report shall also be provided to this advisory committee prior to the annual review, along with any pertinent data from ongoing or completed studies. Additional meetings of the Contractor and the NIAID Advisory Committee for Research on Immune Tolerance may be necessary and will be determined by the Project Officer.
Final Technical Report
At the completion of the contract period, the Contractor shall submit five (5) copies of the Final Technical Report summarizing the results of the entire contract work for the complete performance period. Three (3) copies of the Final Technical Report are to be provided to the Project Officer, and two (2) copies to the Contracting Officer.
The Final Technical Report shall include: (1) a detailed description of the results of all research conducted under this contract; (2) a scientific agenda to accelerate future clinical research on immune tolerance, including: recommendations for the continuation, expansion or termination of clinical trials and mechanistic studies undertaken by the Network; new promising tolerogenic approaches worthy of further investigation; recommendations for the overall design of future clinical trials to evaluate the safety, toxicity and efficacy of promising new tolerogenic approaches; and recommendations for the design of future mechanistic studies and promising techniques; and (3) a discussion of problems and obstacles encountered in organizing, managing and coordinating the activities of the Network, methods used to overcome problems and obstacles, and recommendations for improvements in this approach to integrated basic and clinical research.
Selection of an Offeror for contract award will be based on an evaluation of proposals against two factors. The factors in order of importance are: (1) the overall plan and its comprehensiveness for accelerating research on immune tolerance through clinical trials of the safety, toxicity and efficacy of tolerance induction strategies, and through studies of the underlying mechanisms involved in the induction, maintenance and loss of tolerance; and (2) cost.
Offerors are advised that an award will be made to the Offeror whose proposal provides the best overall value to the Government.
Additionally, evaluation will include the demonstrated capabilities of the prospective Contractor in relation to the needs of the project as set forth in the RFP. The merits of each proposal will be carefully evaluated. Each proposal must document the feasibility of its plan to successfully achieve the objectives of the RFP. Offerors shall submit information sufficient to evaluate their proposals based on the detailed criteria listed below.
a) Identified knowledge gaps and scientific opportunities
b) Scientific agenda, including conceptual framework and approach to mechanistic studies and clinical trials
c) Proposed clinical trials and mechanistic studies
a) Leadership and Management Structure
Proposed scientific, clinical, technical and administrative leadership of the Network. This shall include the documented training, experience, leadership and availability of the Project Director and the overall competence of the Project Director, and the surrounding leadership to successfully manage a project of comparable size and complexity.b) Scientific, Clinical, Technical and Administrative Staff
Documented training, experience and availability of the proposed other professional, technical and administrative staff, documented ability to perform their roles in proposed studies, expertise in similar projects, and the time commitment of the other professional, technical and administrative staff.c) Subcontractors
Documented training, experience and availability of proposed subcontractor(s), their documented capability to perform the proposed work, expertise in similar projects, and the time commitment proposed.Quality of the scientific plan to identify the need to add, replace, or remove scientific and technical staff of proposed subcontractor(s), dependent on progress, performance or changes in scientific direction.
d) Facilities and Resources
Documented availability and adequacy of facilities, equipment and resources necessary to carry out all phases of the proposed projects.
Feasibility of the proposed plan and approach to expand the Network to incorporate research focused on the development and validation of tolerance assays.
Feasibility of the proposed plan and approach to expand the Network to incorporate clinical trials and mechanistic studies in asthma and allergic diseases.
Feasibility of the proposed plan and approach to expand the Network to incorporate clinical trials and mechanistic studies in autoimmune diseases.
Whether you review this draft project requirement as a potential future offeror or as a fact-finding exercise, the NIAID is interested in your feedback. The NIAID is actively soliciting input from academic and industry sources to improve and refine this draft requirement and is seeking to gauge the degree of interest in this effort. PROPOSALS ARE NOT BEING SOLICITED AT THIS TIME. Candid questions and concerns elicited by this notice are encouraged. Comments may address the draft work statement, the technical evaluation criteria, and/or the reporting requirements. The extent to which a dialogue may be established with any individual or business entity concerning a given issue raised by this notice shall, for purposes of fairness and compliance with Agency regulations, be determined by the NIAID Contracting Officer after consultation with the cognizant NIAID Technical Program Office.
Examples of feedback may include, but are not limited to:
Responses should be clear and succinct. We do not desire the submission of any technical or cost proposals. Any critique of the draft project requirement should adequately describe concerns and offer recommendations and/or solutions that might be used by the NIAID in refining the requirement. Critical technical concerns should be supported with questions posed in such a way as to point toward possible alternatives that may be pursued by the NIAID in refining some aspect(s) of the requirement.
Responses should be submitted by 5 o'clock PM EST, on Wednesday, October 14, 1998. All responses should include the name, position/title, telephone/extension, facsimile number(s), and electronic mail address(es) of the contact individual. The response should also identify the institution, organization, company, etc., and the complete street address (including, where applicable, location identifiers, e.g., office stop and room number) including zip code.
All response information should be directed in writing by U.S. mail or electronic mail to:
National Institutes of Health
National Institute of Allergy and Infectious Diseases
Attention: Rosemary Hamill, Contracting Officer
Contract Management Branch (Ref. NIH-DAIT-NIAID-00-07)
6003 Executive Boulevard, Solar Building, Room 3C03
Rockville, Maryland 20852
E-mail: rh26v@nih.gov
Phone: (301) 496-0384
Facsimile: (301) 480-5253