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Special Emphasis Panel of the National Institutes of Health on the Coordination of Rare Diseases Research

 

DEPARTMENT OF HEALTH AND HUMAN SERVICES

NATIONAL INSTITUTES OF HEALTH

REPORT ON STEPS TO COORDINATE RARE DISEASES RESEARCH PROGRAMS:

Analysis by and Recommendations of the Special Emphasis Panel of the National Institutes
of Health on the Coordination of Rare Diseases Research

and

Report on the Rare Diseases and Conditions Research Activities
of the National Institutes of Health, 1999

Foreword


Language from the United States Senate Appropriations Committee report on the budget of the National Institutes of Health (NIH) for Fiscal Year 1996 requested a report on the coordination of rare diseases research. The specific language follows:

"The Committee recognizes that NIH makes considerable resources available to support research on the rare diseases and conditions. The Committee requests that the Office of Rare Disease Research, working jointly with the research institutes and centers of the NIH, and other Federal agencies with recommendations from voluntary health organizations, and the pharmaceutical and biotechnology industries prepare and submit to the Committee prior to the hearings for fiscal year 1997 a report on steps to coordinate rare disease research programs within existing research funds and resources." (Senate Report Number 104-145, pages 110-111)

To respond to this request, NIH, through its Office of Rare Diseases (ORD), convened a Special Emphasis Panel. The Panel met on May 27-28, 1997, and again on March 30, 1998, and developed recommendations for stimulating research on rare diseases and conditions, utilizing research resources, coordinating rare diseases research and development activities, and identifying emerging opportunities in rare diseases research. This report presents the Panel’s recommendations developed at its last meeting. Also attached as an appendix to this report is a copy of the mandated annual report to the DHHS Orphan Products Board on the rare diseases and conditions research activities of the NIH for 1999. This appended report highlights the rare diseases and conditions research efforts in most of the NIH Institutes and Centers for that year, many of which were the subject of the Special Emphasis Panel’s review.

 

TABLE OF CONTENTS

EXECUTIVE SUMMARY

INTRODUCTION

BACKGROUND

RECOMMENDATIONS

EXECUTIVE SUMMARY


INTRODUCTION

Language from the United States Senate Appropriations Committee report on the budget of the National Institutes of Health (NIH) for Fiscal Year 1996 requested a report on the coordination of rare diseases research. The specific language follows:

"The Committee recognizes that NIH makes considerable resources available to support research on the rare diseases and conditions. The Committee requests that the Office of Rare Disease Research, working jointly with the research institutes and centers of the NIH, and other Federal Agencies with recommendations from voluntary health organizations, and the pharmaceutical and biotechnology industries prepare and submit to the Committee prior to the hearings for fiscal year 1997 a report on steps to coordinate rare disease research programs within existing research funds and resources." (Senate Report Number 104-145, pages 110-111)

This report has been prepared by a Special Emphasis Panel (SEP) of the National Institutes of Health (NIH) of the DHHS in response to the Committee’s request. The report describes current research support mechanisms and available research resources. The report also provides recommendations regarding the improvement of coordination of rare diseases research efforts and ongoing programs of the Office of Rare Diseases(ORD)at the NIH. As the Office of Rare Diseases (ORD) continues to carry out its administrative mandate, the recommendations for future activities provided in the report will be carefully considered. However, it is noted that this report does not reflect endorsement of these recommendations by the National Institutes of Health or the United States Department of Health and Human Services. This report presents a series of recommendations expressed by members of a special emphasis panel supported by NIH’s Office of Rare Diseases. The ORD has initiated activities to implement several of the recommendations as funds and staffing levels permit. The focus of the recommendations is primarily on what should be improved and to a much lesser extent on the accomplishments of the Office.

Responsibility for addressing and implementing the recommendations of the SEP will be coordinated by the ORD. A status report on the implementation activities will be provided in the Report to Congress on Rare Disease Research advances prepared by NIH on an annual basis. In recent years, the budget for the NIH research activities has increased significantly. The budget for the Office of Rare Diseases grew from $1.5 million to $1.994 million in Fiscal Year 1999. In Fiscal Year 2000 the budget is $2.07 million. This increase in funds has been devoted to additional support for scientific workshops, a program to increase the number of expert reviewer consultants to assist in the review of grant applications for rare diseases, the expansion of existing ORD databases to link patients and patient support groups with research investigators, and the development of the Gene Vectors for Rare Diseases initiative with the Food and Drug Administration and other Institutes and Centers of NIH.

BACKGROUND

Approximately 20 million people in the United States are affected by an estimated 6,000 rare diseases or conditions. To enhance coordination within the rare diseases community, the Office of Rare Diseases (ORD) established in 1997 the Special Emphasis Panel (SEP) on the Coordination of Rare Diseases Research. Representatives from academic research centers, voluntary patient support groups, the pharmaceutical, biotechnology, and device industries, and other Federal agencies served on this advisory group.

The panel was charged to explore the following:

The Panel met at the National Institutes of Health (NIH) on May 27-28, 1997 and March 30, 1998 and developed 19 recommendations intended to enhance research and coordination in both the public and private sectors. Some of the recommendations are specific to the ORD and the NIH, while others pertain to the rare diseases research community as a whole. In drafting the recommendations, the SEP focused on the importance of advocacy in stimulating the research of rare diseases and the need to meet specific needs for all patients, including the need for:

It is anticipated that an advisory group to the Office of Rare Diseases will monitor the implementation of these recommendations and provide guidance on future activities.

I. Stimulating Research on Rare Diseases and Conditions

  1. Emphasis on Research of Rare Diseases and Conditions

The NIH should continually highlight the significance and importance of clinical research to medicine and health and emphasize that an investigator might conduct basic, clinical, or translational research dedicated to a single rare disorder or a group of related rare disorders over a lifetime career.

  1. Resources for Training Programs

Resources currently available for specific training programs should highlight opportunities in rare diseases research.

  1. Impact of Managed Care on Clinical Research

The ORD should participate in the NIH panel on managed care and clinical research to identify financial barriers to clinical research.

  1. The Peer Review Process

Special emphasis should be placed on recruiting scientists experienced in specific rare diseases or conditions to participate in the review of grant applications, on site visit teams, and as active participants in advisory council proceedings. The Office of Rare Diseases and the Center for Scientific Review at NIH should make special efforts to recruit qualified academic scientists in these areas to participate in the grant review process.

  1. Membership on Advisory Councils

Representatives from voluntary patient support groups should be actively recruited to serve as members of advisory councils at the NIH.

  1. Patient Participation in Clinical Research--Travel to the Research Site

The NIH should provide sufficient resources for travel expenses to patients participating in rare diseases research. The NIH should make information readily available about sources of air travel to research and treatment sites.

  1. Scientific Workshops and Symposia

The NIH and the ORD should expand existing programs to provide support for scientific workshops and symposia to identify research opportunities and to stimulate research in rare diseases and conditions.

  1. Patient Privacy

Privacy and confidentiality must be maintained in all aspects of patient participation in clinical research studies, genetic testing and counseling services, and treatment programs.

II. Utilizing Research Resources

  1. Availability of Research Resources

    The NIH should emphasize the availability of research resources supported by the Institutes and Centers of the NIH. A centralized information database containing research resources should be developed and made available to research investigators, physicians, and patients for their use.

  2. Scientific Materials, Animal Models, and Data Dissemination

    The NIH should develop a program to subsidize and facilitate the development and distribution of reagents, animal models, including "knock-out mice" for rare genetic disorders, and materials for research on rare diseases.

  3. Access to Patented Genetic Materials and the Patent Process

The appropriate organization(s) at the NIH and elsewhere should investigate and evaluate the effect on rare diseases research of patents on genetic material. If flaws exist in the current system, they should be addressed by the appropriate Federal organization.

  1. The General Clinical Research Centers (GCRC) Program

The panel considers the continued operation of the GCRC program as an essential component of research in the United States, especially for genetic disorders and inborn errors of metabolism. Health care providers and the public should have ready access to information on planned and ongoing clinical research studies conducted at the NIH-supported GCRCs.

III. Coordination of Rare Diseases Research and Development Activities

  1. Advisory Group on Rare Diseases Research

The NIH should establish an advisory group to the Director, ORD, to provide recommendations for program activities and to serve as a public forum to discuss needs and issues of the rare diseases community.

  1. Establishing a Permanent Presence for the Office of Rare Diseases at the National Institutes of Health

The NIH should review the existing mechanisms to establish a permanent presence for the ORD and its activities at the NIH.

  1. The Orphan Products Board and the Food and Drug Administration

The Orphan Products Board (OPB) of the Department of Health and Human Services (DHHS) should develop procedures to solicit advice from the rare diseases community.

IV. Identifying Emerging Opportunities In Rare Diseases Research

  1. Specialized Centers of Research and Diagnosis of Rare Diseases

NIH should support the establishment of Specialized Research and Diagnostic Centers of Excellence for Rare Diseases to stimulate research and aid in the diagnosis of rare diseases.

  1. Small Business Innovative Research/Small Business Technology Transfer (SBIR/STTR) Programs

The NIH should emphasize the need for research advances and products for the prevention, diagnosis, and treatment of rare diseases in SBIR/STTR publications and announcements.

  1. Gaining Access to Reliable Information

The NIH and Principal Investigators should update the Computer Retrieval of Information on Scientific Projects (CRISP) summary abstracts of active grants, contracts, and cooperative agreements to include changes in research direction or protocols. The term "rare disease" should be included in the CRISP Thesaurus vocabulary as an identifier for research projects.

  1. Gene Vector Development

The FDA, NIH, the research community, and the pharmaceutical and biotechnology industries should collaborate to facilitate the development of gene vectors to be used for all rare genetic diseases.

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Report of the Special Emphasis Panel on the
Coordination of Rare Diseases Research

INTRODUCTION

Language from the United States Senate Appropriations Committee report on the budget of the National Institutes of Health (NIH) for Fiscal Year 1996 requested a report on the coordination of rare diseases research. The specific language follows:

"The Committee recognizes that NIH makes considerable resources available to support research on the rare diseases and conditions. The Committee requests that the Office of Rare Disease Research, working jointly with the research institutes and centers of the NIH, and other Federal Agencies with recommendations from voluntary health organizations, and the pharmaceutical and biotechnology industries prepare and submit to the Committee prior to the hearings for fiscal year 1997 a report on steps to coordinate rare disease research programs within existing research funds and resources." (Senate Report Number 104-145, pages 110-111)

This report has been prepared by a special Emphasis Panel of the National Institutes of Health (NIH) of the Department of Health and Human Services (DHHS)in response to the Committee’s request. The report describes current research support mechanisms and available research resources. The report also provides recommendations regarding the improvement of coordination of rare diseases research efforts and ongoing programs of the Office of Rare Diseases(ORD)at the NIH. As the Office of Rare Diseases (ORD) continues to carry out its administrative mandate, the recommendations for future activities provided in the report will be carefully considered. However, it is noted that this report does not reflect endorsement of these recommendations by the National Institutes of Health or the United States Department of Health and Human Services. This report presents a series of recommendations expressed by members of a special emphasis panel supported by NIH’s Office of Rare Diseases. The ORD has initiated activities to implement several of the recommendations as funds and staffing levels permit. The focus of the recommendations is primarily on what should be improved and to a much lesser extent on the accomplishments of the Office.

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BACKGROUND

Approximately 20 million people in the United States are affected by an estimated 6,000 rare diseases or conditions. An Amendment to the Orphan Drug Act of 1983 defined a rare disease as one affecting fewer than 200,000 Americans or a disease with a greater prevalence but for which no reasonable expectation exists that the costs of developing or distributing a drug can be recovered from the sale of the drug in the United States(1,2).

The NIH budget for biomedical research has increased significantly in the last 10 years with an increased emphasis by the Congress. The budget for the Office of Rare Diseases grew from $1.5 million to $1.994 million in Fiscal Year 1999. In Fiscal Year 2000 the budget is $2.07 million. This increase in funds has been devoted to additional support for scientific workshops, a program to increase the number of expert reviewer consultants to assist in the review of grant applications for rare diseases, the expansion of existing ORD databases to link patients and patient support groups with research investigators, and the development of the Gene Vectors for Rare Diseases initiative with the Food and Drug Administration and other Institutes and Centers of NIH.

The National Commission on Orphan Diseases reported in 1989 that approximately 18 percent of the NIH research budget supports research on rare diseases and conditions.(3) The Panel is concerned that despite this level of funding for all research, there has been insufficient support for either basic or clinical research at the local and national levels for rare diseases. In the past NIH has made clinical research a high priority both in rare and common diseases. However, the need for research on specific rare diseases is great, and scientific opportunities are many, making competition for available resources fierce for all applications despite a continued increase in research funding. Due to the lack of resources for research, clinical investigators spend less time in their laboratories or on the clinical research unit and more time providing clinical services to patients.

Innovative approaches by the rare diseases community are required to optimize existing research resources. Collaborative research efforts that include individuals with different scientific and clinical training experiences from academic research centers, Public Health Service (PHS) agencies, voluntary patient support groups, and the pharmaceutical, device, and biotechnology industries can enhance research and improve the dissemination of information on research activities. Information sharing is critical for the rare diseases community. Because most rare diseases affect relatively few individuals, public awareness of planned or ongoing research is often lacking. Patients, health care providers, and researchers may be unaware of available resources and support for research from the private and public sectors.

Since its inception, the ORD at NIH has worked to provide leadership, identify and provide resources, and enhance coordination within the rare diseases community. To further enhance coordination within the rare diseases community, the ORD established the Special Emphasis Panel on the Coordination of Rare Diseases Research in 1997. This advisory group is composed of representatives from academic research centers, voluntary patient support groups, the pharmaceutical, biotechnology, and device industries, and other Federal agencies.(The roster of the Special Emphasis Panel is provided as an Attachment.)

The panel was charged to explore the following:

On May 27-28, 1997 the Panel met at the NIH and was briefed on the historical significance of the Orphan Drug Act and recent activities related to the research and development of orphan products in the private and public sectors. Specific topics discussed at the meeting included:

On March 30, 1998 the Panel met again at the NIH to discuss the proposed recommendations and methods to implement them.

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RECOMMENDATIONS

The Special Emphasis Panel on the Coordination of Rare Diseases Research developed 19 recommendations intended to enhance research and coordination in both the public and private sectors. Some of the recommendations are specific to the NIH and ORD. Others pertain to the rare diseases research community as a whole. In drafting the recommendations, the Special Emphasis Panel focused on the importance of advocacy related to stimulating the research of rare diseases and the ways to meet specific needs for all patients, including the need for:

Even though the existing special emphasis panel will not continue as a permanent advisory group to the ORD, it is anticipated that an advisory group will monitor the implementation of these recommendations and provide guidance on future activities. The following sections present the panel’s recommendations, provide information on the issues addressed by the recommendations, and suggest some of the activities to be carried out by the ORD.

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I. STIMULATING RESEARCH ON RARE DISEASES AND CONDITIONS

1. Emphasis on Research of Rare Diseases and Conditions

The Panel believes that resources and support for basic, translational and clinical research of rare diseases and conditions are inadequate. In this report, an emphasis has been placed on clinical research of rare diseases because so much of the research related to rare diseases requires patient participation, if not as participants in clinical trials then as donors of blood or tissue samples. Many consider translational research (both basic to clinical and clinical to basic) as the real "no person’s land" of research support in need of considerable emphasis to reflect adequate support.

Remarkable treatment advances have been realized in several rare diseases. For example, cystic fibrosis and sickle cell disease demonstrate the progress that can be made when adequate support is made available through "special" emphasis on a particular disorder and a coordinated public sector/private sector research program is developed and implemented. Basic, translational, and clinical research all move ahead and not as separate entities requiring an extended period of time to complete each project. Voluntary patient support groups must be viewed as active participants in the research process. The pharmaceutical, biotechnology, and medical device industries also must share in the numerous research and development phases of research. Successful research efforts result when all interested resources obtain ownership in the research and development process. Each participant must be viewed as a key element contributing to a successful program to develop interventions to prevent, diagnose, or treat rare diseases or conditions.

Recommendation:

Approximately 30 percent of all NIH funded research is directed to clinical research projects. The definition of clinical research stated below, was adopted by the NIH Director’s Panel on Clinical Research in its December 1997 report to the Advisory Committee to the NIH Director.(4)

Clinical Research has three subtypes:

If treatment of rare diseases is to advance, a balance must be maintained between basic and clinical research. The NIH receives far more grant applications for basic research, most often conducted by investigators with Ph.D. degrees, than it receives for clinical research, most often conducted by scientists with M.D. degrees. However, competition for funds is similar for both basic and clinical research and both types have approximately the same success rate in obtaining grant support. Despite this parity in funding rates, surveys show less significance is placed on the importance of clinical research as opposed to the emphasis on basic research.

Recent trends from 1994-1997 indicate a 31 percent decline in the actual number of first time physician applicants for NIH research grants. There was no increase in the number of applications from physicians with a Ph.D. degree.

Other data indicate that fewer graduate physicians are interested in careers as independent NIH supported research investigators. There has been a 51 percent decrease (from 2,613 to 1,261) in the total number of physician post-doctoral trainees receiving support from NIH fellowships and training grants. Additionally, interest in biomedical research as a career is not increasing among medical school graduates. The total number of medical school graduates who have a strong interest in biomedical research as a career choice has declined from 14 percent in 1989 to 10 percent in 1996.

In 1994, a study group analyzed the review of patient-oriented grant applications, and the group's findings substantiated this difference in emphasis. The analysis revealed that 23 study sections reviewed two-thirds of all clinical research applications. Nineteen study sections reviewed no clinical research applications. Forty-nine study sections reviewed one-third of the clinical research applications with density ranging from one to 30 percent. Those clinical research proposals reviewed by the study sections that review a lower percentage of clinical research grants (less than 30 percent) as part of their total review responsibilities did not fare as well in the review process as non-clinical research proposals. Non-clinical research applications have a two-fold success advantage when they are reviewed by a section with a high density of clinical research protocols.(5)

This concern and apparent bias against clinical research prevails throughout the research community and is not limited to the awarding of grants. At most academic institutions, the contributions of clinical researchers, either as individuals or as participants in multi-center clinical studies, are often considered to be less significant than the contributions of individual scientists conducting basic research. Promoting the role of translational and clinical research along with all other research activities as well as understanding the need for multi-center clinical research studies of most rare diseases, will help change these attitudes.

Additionally, the NIH must emphasize that the research community needs to acknowledge the dedication and the significant contributions that clinical investigators have made to biomedical research. Successful investigators can suggest how advances in research can be applied to both rare and common disorders and how scientific advances from basic research can be extended to clinical applications. Individual investigators are valuable resources and the infrastructure that supports research, especially rare diseases research, must emphasize the value of their knowledge and expertise that may have been acquired over a lifetime career dedicated to researching a single rare disorder or a group of related rare diseases. This message must be communicated, whenever possible, in NIH-sponsored publications, conferences, and workshops.

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2. Resources for Training Programs

Recommendation:

There has been widespread concern about the shortage of clinicians pursuing careers in clinical research, and more specifically, involvement in research of rare diseases. The NIH recently announced three new types of career development awards that are intended to increase the clinical researchers' participation in medical research. The awards will serve as important additions to the NIH's efforts to enhance and expand clinical research training and career development. The K awards described below should complement the activities of the Specialized Research and Diagnostic Centers of Excellence for Rare Diseases Research presented later in the report. The mentored training awards could prove to be an essential component in training and developing the next generation of physician-scientists committed to the investigation of rare diseases and conditions. Every Institute will use these core training awards, and the NIH expects to begin funding the new awards in Fiscal Year 1999.

The NIH Clinical Center Hospital could also continue to serve as a special training center for researchers dedicated to the investigation of rare diseases.

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3. Impact of Managed Care on Clinical Research

Recommendation:

A majority of Americans now receive health care services from managed care organizations (MCOs). A major concern for patients with rare diseases who receive medical care from an MCO is the inability to gain access to clinicians or research investigators skilled in diagnosing and treating rare disorders. This adverse effect of MCOs falls disproportionately upon patients with rare diseases. Persons with common chronic or acute disorders do well with most competent care givers. Persons with most rare disorders, however, require the services of an appropriate specialist who, because of training and experience, can properly recognize and manage the specific rare disorder. Appropriate specialists are also needed for treatment purposes, which may require that the patient be referred to a physician not included in the specific plan's usual panel. Patients must be allowed to receive ongoing treatment in specialized clinics or from experts in specific rare diseases to ensure appropriate follow-up care. When MCOs deny referrals or benefits to rare disease patients who must then go "out of network" to obtain appropriate medical care, patients are thereby denied the benefits that persons with common disorders can derive while remaining in the network.

MCOs need to be responsive to the needs of patients who wish to participate in clinical trials. Patients receiving treatment from MCOs may not have ready access to clinical trials and patient referral services. For many patients with rare diseases, clinical trials serve as treatment options, especially when no other intervention is available, and treatment outcomes may be better during and after their participation in a clinical trial. Patients with rare diseases need to be informed about these options. Information that might not routinely be transmitted in the managed care and the non-managed care environments should be made more readily available.

The American Association of Health Plans (AAHP) has signed an agreement with NIH to find ways to increase patient accrual into clinical trials supported by the NIH. Details of an implementation plan are currently being developed and negotiated. AAHP represents more than 1,000 MCOs and other health plans that provide health coverage for more than 140 million Americans. Several groups do support medical research and participate in NIH-supported clinical trials. A formal proposal for partnership between AAHP and the NIH to support clinical research has been developed.

Access to Clinical Trials Supported by The National Cancer Institute

Due in part to the National Cancer Institute's (NCI) efforts, Medicare patients can now enroll in NCI sponsored clinical trials. Additionally, the Department of Defense (DoD) and the Veteran's Administration (VA) are collaborating with NCI to enroll patients and will reimburse for patients' health care while they are in clinical trials.

On March 5, 1996, NCI and the DoD signed an interagency agreement, formalizing the process that gives thousands of DoD cancer patients more options for care and greater access to state-of-the-art treatments. This agreement could serve as a model for future partnerships between the insurance industry and the medical research community.

The agreement includes a DoD demonstration project that allows patients who are beneficiaries of TRICARE/CHAMPUS (Civilian Health and Medical Program of the Uniformed Services), the DoD's health program, to participate in NCI-sponsored clinical treatment trials. In the past, DoD regulations limited the amount the DoD could reimburse for costs for medical care delivered as part of a clinical trial.

Under the new demonstration project, if a DoD patient is considering participating in a clinical trial, his or her physician will determine which NCI clinical trial might be appropriate and what institutions are enrolling patients in that trial. The physician will then obtain DoD approval and arrange for the patient to be evaluated at the institution selected. Physicians at that institution will then determine whether the patient is eligible for the study.

About 30,000 cancer patients enroll in NCI clinical trials each year. Increased use of managed care plans, which often limit coverage for experimental therapies, could jeopardize patients' access to promising new approaches available in clinical trials and compromise the progress of cancer treatment research. The agreement with DoD is another step to ensure that a sufficient number of patients will be enrolled in the trials to enable researchers to answer vital questions about cancer.

Because clinical demands are greater for many practitioners within MCOs, they have less time for research. The NIH should inform MCOs about the opportunities for participation in research projects involving multiple research sites or multi-center research investigations and encourage participation of MCO patients and physicians experienced in clinical research procedures. The NIH should try to increase the MCO executives' awareness of the rewards of clinical research by including MCO executives in the research planning and decision making processes and by inviting the executives to participate in NIH advisory council meetings.

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4. The Peer Review Process

Recommendation:

Peer review plays an important role to ensure the optimal use of resources, especially in reducing duplication of research of the more common disorders and in recognizing research opportunities presented by rare diseases or conditions. Including experts in rare diseases in the peer review process can greatly enhance the process. To ensure that adequate peer review occurs, the panel recommends that the pool of qualified individuals available to participate in the peer review process be increased and that expert reviewers with a focus on rare diseases be encouraged to participate on site visit teams.

Reviewer Consultant File

Special efforts should be made to continually expand the pool of reviewers/consultants available to participate in the initial review groups (study sections). To provide adequate scientific and clinical expertise for the scientific review process for both basic and clinical research of rare diseases, the ORD should assist the Center for Scientific Review at the NIH in expanding the rare diseases Reviewer Consultant File to include more experts on rare diseases. Expanding the file should be an ongoing activity, and the voluntary patient support groups that have established medical and scientific advisory boards should assist ORD in the expansion process. Scientists, universities, professional societies, and journal editors should also be encouraged to nominate potential reviewers. The FDA's Office of Orphan Products Development's review process is conducted similarly to the NIH's review process.

Site Visit Teams

Investigators with clinical or scientific expertise, especially those experienced in the investigation of rare diseases or conditions, are beneficial to both the reviewing and planning process for public and private sector research projects. Investigators can effectively provide input by participating on a site visit team.

Because there are many diseases under investigation and many organizations including the NIH, other Federal agencies, the pharmaceutical, biotechnology, and medical device industries, foundations, and voluntary patient support groups supporting research, many research investigators are needed to visit sites during the peer review process. The recommendations and findings of a site visit team may play a major role in the laboratory's or clinic's ability to obtain financial support for a grant application. Research investigators involved in scientific investigation of rare diseases must be available to assist in this interactive process and strategies must be developed to increase their participation.

The panel commends the Center for Scientific Review's (CSR) efforts to respond to recommendations from the Report of the NIH Director's Panel on Clinical Research.(6) Several actions to improve the application review process are addressed in these responses provided by CSR:

The Low-Density Study Section Problem

Of special interest are those clinical research areas in which the diversity of expertise required (disease, organ system, biology, technology) precludes sufficient commonality to form a cohesive cluster of grant applications. The CSR provided plans to NIH to test several possible approaches to address the problem. These approaches include:

Large Clinical Trials, Health Services Research, and Outcomes Research

To deal with the issue of large clinical trials, health services research, and outcomes research, CSR will establish a new Special Emphasis Panel(SEP), to review these types of research applications. The members of the SEP will be experts in designing and executing such trials. CSR anticipates having clinicians experienced in conducting clinical trials serve as the principal reviewers. Appropriate experts in statistics and epidemiology will also be asked to serve as members. Due to the diversity of the clinical research to be reviewed by this SEP, CSR will rely heavily on ad hoc reviewers with specific scientific and clinical expertise.

The review panel for large clinical trials could be expanded to accommodate the review of multi-center studies of rare diseases. Usually, no single research site has access to a large enough population of patients with a rare disease. The expertise present on this review panel could prove to be very beneficial to researchers who may elect to conduct a study under a common research protocol at multiple settings to facilitate the enrollment of a sufficient number of patients to complete a clinical trial as quickly as possible.

Approximately 75 to 80 percent of grant applications are not funded following submission of the initial grant application. The Principal Investigators are encouraged to address the concerns expressed by the Initial Review Group and resubmit the grant application. Many resubmitted applications eventually receive support but are now limited to two review cycles per application. It is, therefore, of great importance to include reviewers with special understanding of the technical constraints and also of the potential benefits of rare diseases research as members of the initial review group.

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5. Membership on Advisory Councils

Recommendation:

The second level of review in the peer review process is the advisory council. At this level, program activities are reviewed and recommendations made to assist the NIH Institutes and Centers(ICs)in establishing research priorities and relevant areas for future research directions. Representatives from voluntary patient support groups should be active members of ICs' advisory councils so that the representatives can provide their unique perspective to the review process. Nearly one-third of the members of an advisory council are lay persons with an interest in a particular disorder or from a research foundation, and the NIH strives to maintain this level of participation. Significant public participation beyond the normal public comment period must be solicited for the advisory councils' meetings on issues considered to be of interest to the rare diseases community.

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6. Patient Participation in Clinical Research - Travel to the Research Site

Recommendation:

One of the unique challenges for rare diseases research is the inadequate concentration of patients around a single research site. From the investigator's perspective, an adequate number of patients are needed for the protocol design to be successful. In addition, patients may experience a lack of treatment options in their own local geographical area. A research study protocol thousands of miles away may be their only treatment opportunity. This often results in the patients having to travel thousands of miles at their own expense to participate in a clinical trial for their specific disease. NIH should continue to make sufficient resources available to expand patient recruitment activities into research programs at the NIH Clinical Center Hospital.

For many patients and family members, the expenses required to travel to a research site are an obstacle that cannot be overcome. In recent years, fewer and fewer research projects have sufficient resources to reimburse patients and a family member for travel expenses to the research institution. Therefore, patients and their families or healthcare providers may need to locate alternative sources for these services or expenses. Several voluntary pilot organizations and commercial airline carriers provide charitable and emergency medical flights to enable patients to receive treatment and participate in clinical research projects. The NIH should make information about these resources widely available to health care providers, research investigators, the voluntary patient support groups, and the public. By involving local physicians in ongoing research projects through training programs or network telemedicine capabilities, follow-up care can be provided at a local level and can reduce the patient expenses of participating in clinical trials.

Several alternatives to lengthy travel for patients do exist. One suggestion is to increase the collaborative efforts among several different investigators at multiple research locations. This collaboration requires considerable coordination of research programs with numerous co-investigators and approval from a similar number of Institute Review Boards (IRBs). Another option is to develop a series of specialized research centers geographically distributed around the nation and focused on a cluster of disorders.

Funding of research should include justifiable travel costs to ensure adequate patient participation and rapid completion of clinical studies. Principal Investigators should be encouraged to include the anticipated costs for travel in the grant application's proposed budget, and travel expenses should be based on the projected nationwide recruitment of patients to ensure that enough patients are available so the investigation can be successfully completed. The Initial Review Group should recognize without bias that research investigators need to recruit an adequate number of patients with specific rare diseases. The presence of an active voluntary patient support group plays an essential role in recruiting patients for a clinical study. Proof of ready access to a voluntary health organization should be addressed in a grant application to eliminate any concern about the lack of patients for participation in a clinical research study.

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7. Scientific Workshops and Symposia

Recommendation:

The NIH recognizes the value of supporting scientific meetings, conferences, and workshops that are relevant to its scientific mission and therefore to public health. The NIH has specific guidelines to apply for NIH support for scientific meetings. The guidelines do not apply to other types of conferences, workshops, or scientific meetings sponsored or initiated by the NIH and funded by contracts or by direct operating funds, or workshops conducted as an adjunct to scientific peer review group activities.

The ORD supports scientific meetings depending on the interests and priorities of the individual research ICs and the ORD. ORD gives primary consideration to meetings on rare diseases or groups of diseases for which current research activity is lacking or lagging or for which research will be stimulated as a goal and an outcome of the meeting. The participation of voluntary patient support groups, other Federal agencies with a research or regulatory interest and the pharmaceutical, biotechnology, and medical device industries is strongly encouraged in the planning and development of the workshops.

The ORD considers support for scientific workshops and symposia to be a major activity worthy of a significant portion of its annual budget. Rare diseases are often viewed as models for more common diseases. For many disorders, the workshops offer both basic and applied research investigators the opportunity to determine the current state of research, clinical care, and opportunities and direction for future research. The ORD has cosponsored, along with 17 NIH research ICs, 208 workshops and symposia related to rare diseases. The ORD co-sponsored 15 workshops and symposia in fiscal year 1995, 32 in fiscal year 1996, 27 in fiscal year 1997, 32 in fiscal year 1998, 52 in fiscal year 1999 and 50 in fiscal year 2000. Frequently, additional financial support is provided by several cosponsoring ICs and demonstrates trans-NIH partnerships.

Following each meeting, the ICs provided summaries and information on planned initiatives. These reports are then made available on the ORD web site on the Internet. Several of the outcomes of the meetings include:

The National Commission on Orphan Diseases Report stated that many of the barriers to progress in understanding rare diseases and treating patients are caused not only by a lack of funding but also by a lack of coordination of existing resources. Understandably, researchers may be reluctant to share information, especially if their research ideas are being considered for funding or a pharmaceutical product is in the research and development stage. The ORD anticipates that the scientific and clinical exchange at workshops and symposia will contribute to greater coordination and information sharing among researchers and will facilitate scientific collaboration.

Additionally, even though many of the processes related to orphan products development have now been institutionalized at Federal agencies, a need remains for continued dialogue between the Federal and private sectors to stimulate the development of orphan products. Workshops provide a forum for this dialogue.

An evaluation of the effectiveness of scientific workshops as a mechanism to stimulate research on rare diseases is underway to assist in making the workshops even more effective in the future.

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8. Patient Privacy

Recommendation:

Patient privacy must be maintained in all aspects of genetic testing, counseling, and treatment programs. Of serious concern to patients and their families is the possibility that insurers or employers may discriminate against patients and their families because of their genetic makeup that will impede equal access to both employment opportunities and health insurance. Additionally, patients may be reluctant to participate in clinical research studies due to possible breaches of confidentiality. The National Human Genome Research Institute has the lead role at the NIH in the study of the "Ethical, Legal, and Social Implications" (ELSI) of human genome research. The Institute has joined with others to stimulate legislation to protect individuals from discrimination based on any medical information and the possible manifestation of a disorder at any time during an individual's life. The legislation should address discrimination in employment, educational opportunities, and health and life insurance.

Four bills have been introduced to the 106th Congress to address the concerns in The Health Insurance Portability and Accountability Act of 1996 (HIPAA), but none have received final action. Most states have now enacted HIPAA-conforming legislation. In addition, thirty states have enacted legislation regarding genetic discrimination and insurance, and there continues to be a high degree of interest in this topic in the state legislatures. In the 1999 state legislative sessions, there have been over 100 bills regarding genetic discrimination in the workplace and/or genetic discrimination by insurers. Twenty states have enacted legislation regarding genetic information and the workplace. Some of these state bills would inaugurate genetic anti-discrimination protection, while other bills would modify or clarify existing anti-discrimination legislation.

The Health Insurance Portability and Accountability Act of 1996 (HIPAA) made confidentiality of patients' medical records a priority for Congress. The Secretary of Health and Human Services presented a report to Congress entitled "Confidentiality of Individually Identifiable Health Information" in 1997. This report presents specific recommendations for Federal legislation to protect the privacy of health information. HIPAA stipulates that if Congress did not enact legislation to protect the confidentiality of individuals health information by August 1999, the Secretary of HHS shall promulgate regulations for this purpose by January 1, 2000. Several comprehensive privacy bills have been introduced to the 106th Congress. In addition to these Privacy bills, other bills referred to as "Patients' Bill of Rights" have been introduced that contain provisions regarding medical records privacy and confidentiality.1

__________________________________
1 On December 20,2000, after the completion of this report, the President released a final regulation establishing federal privacy protections for personal health information.

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II. UTILIZING RESEARCH RESOURCES

9. Availability of Research Resources

Recommendation:

The NIH provides considerable support for different types of research resources. Many of these resources are considered crucial for the continued research and development of products for the prevention, diagnosis, and treatment of rare diseases. The NIH should continue to support the development of animal models, cell lines, brain banks, tissue registries, patient registries, and other scientific databases that constitute essential research resources. In addition, to maximize the distribution and use of these resources, more publicity about the existence and availability of these resources must be provided to the research community, to voluntary patient support groups, and to the public. These resources include:

The NIH and the ORD should develop a comprehensive database of existing registries and research resources available in both the private and public sectors. Information from this database should be readily available to research investigators and the rare diseases community. The Internet and World Wide Web and the ORD site will continue to facilitate communications about these numerous resources.

Cell, Tissue, and Patient Registries and Brain Banks

Cell, tissue, and patient registries and brain banks are most valuable research resources and access to these resources often stimulates research on rare diseases. The NIH and many other organizations support the development and maintenance of these registries and databases. The NIH ICs are encouraged to increase the development of cell, tissue, and patient registries and brain banks when possible and promote the availability of these resources. The NIH must convey to investigators how these resources can enhance research, and the NIH must also communicate to patients and voluntary patient support groups their role in developing, contributing to and maintaining cell, tissue, and patient registries and brain banks.

To increase awareness of these resources and their importance, the panel recommends several activities. The ORD should cosponsor a scientific workshop with other ICs of the NIH, other Federal agencies, and the private sector to review these activities and design mechanisms to promote the research resources that are available to research investigators and the rare diseases community. At that time, existing banks and registries must be assessed to determine their adequacy. If deficiencies are identified, the NIH and the ORD should consider providing resources to address these deficiencies and possibly support more comprehensive cell, tissue, and patient registries and brain banks for rare and genetic disorders. For example, a registry of "unknown" birth defects, searchable by the known defect, symptom, or accompanying laboratory results, would assist clinicians in diagnosing birth defects. On the basis of a few symptoms, conditions could be identified even though they may not yet be clearly diagnosed.

Also, the ORD should inform investigators and voluntary patient support groups with specific interest in rare and genetic disorders about the availability of information on cell, tissue, and brain or other specimen banks and reagents for genetic testing. Patients should be encouraged to donate biological specimens to these repositories.

Autopsy

Research resources come from many different sources. A frequently overlooked resource is the usefulness to research of biological materials gained from an autopsy. Efforts should be made to enhance public understanding of the importance of autopsy materials to the advancement of rare diseases research. The appropriate harvesting and preservation of materials is vital and public support for transferring bodies or materials should be increased.

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10. Scientific Materials, Animal Models, and Data Dissemination

Recommendation:

If they have access to financial and technical help to develop critical reagents and materials, investigators may be more likely to pursue programs of research on rare diseases. Reagents and materials relevant to rare diseases include: complementary DNA (cDNA); monoclonal and polyclonal antibodies to various epitopes of proteins; expression vectors, particularly those that provide conditional expression; and antisense constructs. Specific examples of efforts that would support the development and distribution of reagents and materials include:

Subsidizing these or similar efforts might logically be integrated with support of a centers of excellence for research on the particular rare disorder.

The sharing of materials, data, and software in a timely manner has been an essential element in the rapid progress in genomic research. The Public Health Service(PHS) policy requires that investigators make unique research resources, including DNA sequences and mapping information, readily available once their research findings have been published. To ensure the availability of, and access to, the results of publicly funded research, the NIH requires applicants who respond to RFAs to propose specific plans for sharing the data, materials, and software generated through the grant. For example, all data pertaining to Single Nucleotide Polymorphisms (SNPs) are placed in a common, public database that is made available for further research and development, and it is the NIH's intent that human genomic DNA sequence data, generated by projects funded by the ICs, be released as rapidly as possible and placed in the public domain where it will be freely available. Any additional information known, such as map location, should also be made available. When appropriate, grantees may work with the private sector to make unique resources available, at a reasonable cost, to the larger biomedical research community. If they have adequate justification, applicants may request funds to defray the cost of sharing materials or submitting data.

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11. Access to Patented Genetic Materials and the Patent Process

Recommendation:

The Human Genome Project, initiated in 1990, is an international research effort primarily supported by the National Human Genome Research Institute (NHGRI) of the NIH and the Department of Energy (DOE). Major goals of the project are to generate maps of the human genome and to produce the complete sequence of a human DNA by the year 2002.

Since the program's inception, both NHGRI and the research community have expressed concerns about access to patented genetic materials and the sharing of data, materials, and software. NHGRI and the NIH believe there are strong scientific arguments that support making human genomic DNA sequence data freely available and in the public domain. They include:

It takes a long time for patent applications to be reviewed and patents to be issued. It is in the best interest of the rare diseases community that patent applications be reviewed quickly. After a patent has been issued, it is in the public domain for all to review. Researchers can then use the patented products to advance research. A major concern is the length of the review period prior to the issuing of a patent. This review period is viewed as a major impediment to research advances. When possible, the alternative seven-year exclusive marketing provision of the Orphan Drug Act should be utilized as a mechanism to stimulate the development of products for rare diseases and conditions.

The first patent applications in the field are believed to have been filed in June 1991 and were related to the Expressed Sequence Tags (EST) technology that originated in an NIH laboratory at the National Institute of Neurological Disorders and Stroke(NINDS). At the time, it was feared that public disclosure of selected sequences could create a prior art effect against subsequent patenting of newly discovered complete gene sequences possessing important diagnostic or therapeutic utilities. (Prior Art can be interpreted as the existing information against which an invention is judged to determine if the invention is patentable as being novel and unobvious.) Patent applications were filed primarily to provide short-term insurance against potential prior art blockage of future gene discoveries. At the time of the NIH filings and continuing throughout the period of patent examination, the Court of Appeals for the Federal Circuit rendered a series of opinions drawn to DNA/protein sequences, that reduced concerns relating to prior art. The court decisions, along with changes in the NIH patent policy of moving away from patenting research tools, resulted in the NIH's abandoning all pending EST patent applications.

According to the Bayh-Dole Act, grantees have the right to elect to retain title to their inventions and can apply for patents, should additional biological experiments reveal the patent's utility. However, it is the NIH's opinion that raw human genomic DNA sequence, in the absence of additional demonstrated biological information, lacks specific utility and is an inappropriate material for patent filing. The NIH is concerned that patent applications on large blocks of primary human genomic DNA sequence could reduce the development of useful products, since companies may be unlikely to pursue projects for which patent protection is unavailable. The NIH grantee institutions are required to disclose each invention within two months after the inventor discloses the invention in writing to the grantee institution personnel responsible for patent matters. The NIH monitors grantee activity to determine whether attempts are being made to patent large blocks of primary human genomic DNA sequence.

It is essential that Federal regulations on patenting evolve in concert with other material and international legislation affecting Federally funded researchers, the private sector's supported investigators, and those supported by international sources. However, private persons or companies that do not receive Federal support are not prohibited from applying for patents.

The Orphan Drug Act of 1983 and its amendments provide incentives to stimulate the development of products for rare diseases and conditions. This program is administered through the Office of Orphan Products Development at the Food and Drug Administration. The developers of products for rare diseases and conditions are encouraged to apply for Orphan Product Designation prior to submitting the New Drug Application (NDA) with the knowledge that a seven-year period of marketing exclusively is available to sponsors of designated orphan products. Utilization of this provision of the Orphan Drug Act has been the most powerful stimulus to the research and development of products for rare diseases. This provision of the legislation does not extend the patent life of a product. Rather, it provides an incentive for sponsors to develop products for rare diseases and conditions by prohibiting entry of the same product for the same indication for use into the marketplace for a period of seven years from the date of approval of the New Drug Application or the Biological License.

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12. The General Clinical Research Centers (GCRC) Program

Recommendation:

GCRCs serve as major research sites for rare diseases. The NIH, through the National Center for Research Resources (NCRR)and the GCRC program, supports approximately 75 GCRCs in the United States. Most are located within hospitals of academic medical centers. The GCRC-based investigators perform interdisciplinary inpatient and outpatient clinical research supported by the NIH, the pharmaceutical industry, or other funding sources. Also, the NIH supports research activities by providing specialized research laboratories for database management and analysis services, and research personnel, such as biostatisticians and specially trained research nurses. The established centers compete for NIH support, and each year the NIH may add new centers to the GCRC program and discontinue funding to others.

The GCRCs multi-center approach is key to rare diseases research because these large populations of patients, centered at one location in the United States, who have a particular disease, do not exist. The GCRCs offer a very practical venue for attracting patients from diverse geographic locations and research investigators from multiple disciplines to merge at a single site in conjunction with other sites in a common research protocol. The panel considers the continued operation of the GCRC program to be an essential component of research in the United States for genetic disorders, inborn errors of metabolism, and other rare diseases. Gene therapy research is also conducted at the GCRCs, and this research is expected to expand, especially in the area of gene vector development with special attention here to rare diseases. This is particularly important for Federally funded GCRCs because the private sector provides greater support for gene therapy research on the more common diseases as compared to the rare diseases.

Health care providers, patients and their families, and the general public are able to gain public access to detailed information about planned and ongoing gene transfer clinical trials involving rare diseases at NIH-supported GCRCs. Public disclosure of gene transfer clinical trial information is ensured through compliance with the NIH Guidelines for Research Involving Recombinant DNA Molecules (NIH Guidelines) by NIH-sponsored institutions. The NIH office of Recombinant DNA Activities (ORDA) is responsible for the administrative oversight of gene transfer clinical trials involving rare diseases.

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III. COORDINATION OF RARE DISEASES RESEARCH AND DEVELOPMENT ACTIVITIES

13. Advisory Group on Rare Diseases Research

Recommendation:

Many of ORD's activities meet the needs of the rare diseases community. These activities are the direct result of recommendations developed in 1989 by the National Commission on Orphan Diseases (NCOD) and from testimony provided at public meetings of the DHHS's Orphan Products Board. Currently, there is no formal process to facilitate the ORD's receipt of suggestions from the rare diseases community.

An advisory group to the Director, ORD, should be established. The advisory group should provide guidance for implementing the recommendations received from this Special Emphasis Panel and the NCOD and serve as a public forum in which the needs and issues of the rare diseases community are discussed. This forum could also help the research community avoid duplicating activities in the private and public sector. Members of this advisory group should include representatives from voluntary patient support groups, clinicians and research investigators familiar with rare diseases; pharmaceutical, biotechnology, and medical device industries, private foundations, MCOs, NIH, and other Federal agencies involved in rare diseases research.

Consumers representing the interests of patients with rare diseases should seek active roles on all NIH advisory groups, including Institute and Center advisory councils as well as the Advisory Committees to the Director, NIH.

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14. Establishing a Permanent Presence for the Office of Rare Diseases at the National Institutes of Health

Recommendation:

The panel identified specific activities for the ORD. The ORD should maintain an active presence in the extramural and intramural research activities of the NIH and be aware of the problems related to the research of rare diseases. ORD should expand efforts to increase collaboration of extramural and intramural investigators and NIH-supported research resources. To promote interaction between investigators and the voluntary patient support groups, more interactive scientific workshops and meetings should be held and investigators and support groups should be encouraged to participate. Specific activities carried out on an ongoing basis should include:

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15. The Orphan Products Board and the Food and Drug Administration

Recommendation:

In March 1982, DHHS created the Orphan Products Board (OPB) to promote the development of drugs for rare diseases and coordinate the development for orphan drugs among Federal agencies, manufacturers, and voluntary organizations. The OPB, established before the Orphan Drug Act became law, is mandated to coordinate all Federal programs involved in orphan product development and rare diseases research. It advises the Assistant Secretary for Health on orphan drug issues.

The OPB has representatives from several Federal agencies: FDA, NIH, Centers for Diseases Control and Prevention (CDC), DoD, DOE, Health Care Financing Administration (HCFA), and VA. Currently, the OPB has no public members and no representatives from voluntary patient support groups, foundations, or the pharmaceutical, device, and biotechnology industries.

Usually, one meeting a year is conducted as an open meeting and throughout the year other participants are invited to OPB meetings to provide input on specific topics. The OPB has no regulatory authority. The OPB is required to submit an annual report on research advances and orphan product designation made by the FDA, and to recognize accomplishments in research on rare diseases.

The Panel recommends that membership of the OPB should include consumers, industry representatives, academic researchers, professional associations, and others who have an interest in the development of products for rare diseases and conditions. The OPB and the Advisory Group to the Director, ORD, should coordinate their activities and meetings whenever possible to facilitate cooperation between NIH grantees and the FDA in the development of rare diseases clinical trials and related activities of special concern is the need to expand gene therapy trials to include rare diseases in the research plans of the NIH research institutes.

The FDA plays an important role in clinical research. Prior to initiating a clinical trial, principal investigators must obtain approval from the local Institutional Review Board (IRB). Additionally, the investigator must also receive authorization from the FDA to use an investigational product before proceeding with the study. In many cases, investigators use information contained in their grant application in their request for authorization to use an investigational product. Patient consent forms and plans for monitoring safety and efficacy may also be drawn from the grant application. The research and development of new technologies may require specific ethical reviews of protocols as well as scientific reviews.

Representatives from the NCI's Division of Cancer Therapy and Evaluation Program meet monthly with the FDA to discuss potential problem areas. ORD could explore whether this model could be adopted by more of the research institutes of the NIH. The review divisions of the FDA provide information on the adequacy of the study protocol received from investigators as part of the Investigational New Drug, Medical Device, or Biological Product review process. If investigators are uncertain about the content of a study protocol, they can ask for and receive a written response from the FDA. Investigators are encouraged to discuss research plans with the FDA review division responsible for the evaluation of the investigational product, including safety and outcomes measurements. The FDA's Office of Orphan Product Development (OOPD) serves as a liaison for the research institutions, the investigator, and the FDA review division. The review divisions of the FDA should continue to facilitate the review of investigational products and requests for pre-marketing approval of orphan products. The FDA has a commendable record of approval of approximately 175 orphan products since the Orphan Drug Act was enacted in 1983.

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IV. IDENTIFYING EMERGING OPPORTUNITIES IN RARE DISEASES RESEARCH

16. Specialized Centers of Research and Diagnosis of Rare Diseases

Recommendation:

For many of the more common disorders, such as some cancers, heart diseases and disorders, diabetes, and ophthalmological conditions, specialized centers of research have been established and have stimulated research. Research resources for studies of patients with rare diseases could be used more efficiently, if more multi-center studies are conducted. The Panel realizes the current budget does not provide sufficient funds for these Centers. Resources within the President's current budget for the NIH, in addition to ORD's budget, are needed to develop Specialized Research and Diagnostic Centers of Excellence for Rare Diseases. The development of these centers is considered a crucial recommendation to coordinate research on rare diseases. These activities would meet critical research needs by fostering research on rare diseases and by developing research facilities specifically for research on rare diseases. One of several centers could be located at the NIH Clinical Center Hospital. These facilities would also serve as a training ground to develop new investigators under the mentoring of established investigators with experience in rare diseases research. Support would be provided to coordinate the activities of the research centers in the United States and would make investigational treatments more accessible to patients with rare diseases.

These Centers of Excellence would also help patients to obtain a correct diagnosis. The National Commission on Orphan Diseases found that 15 percent of patients with rare diseases did not obtain a correct diagnosis until after five years or more. An additional thirty percent of the patients waited from one to five years before obtaining a diagnosis. The other 50 percent of the patients received a timely diagnosis within a year of their initial visit to their physician.

One possible approach would be to fund Specialized Research and Diagnostic Centers of Excellence for Rare Diseases for major categories of rare diseases (e.g., inborn errors of metabolism). These centers would bring together persons skilled in diagnosing and treating a group of rare diseases. Additionally, bringing together groups of patients with similar or related disorders will foster basic scientific investigation, permit synergy in translational research, and enhance opportunities for collaborative clinical investigation. The intramural research staff at the National Institutes of Health might also meet this need in a more formal operating unit at the Clinical Center hospital.

Another approach could involve the use of established GCRCs and other special centers of research to provide an infrastructure for the establishment of research and diagnostic services related to rare diseases. Creative cooperative efforts among the ORD, the research ICs of the NIH, and the academic health centers could establish these centers if adequate funds are made available for this initiative. Specialized Centers of Research, Core Research Centers, Pediatric Clinical Pharmacology Research Centers, and other research centers receiving support from the NIH may serve as models for the rare diseases research centers of excellence. Increased collaborations may allow regional or national Institutional Review Boards(IRBS) to be utilized to help reduce the required paperwork investigators must submit prior to initiating a study at multiple research sites.

Barriers to Rare Diseases Research and a Proposed Solution

Many barriers to rare diseases research have been identified and include decreased time available for clinical research, inadequate funding for clinical research, and lack of adequate space and facilities for clinical research. Each of these issues is discussed briefly and a possible solution to establish centers of research excellence for rare diseases is presented.

Barriers to Rare Diseases Research

Decreased Time Available for Clinical Research

Funding for Clinical Research

Space/Facilities for Clinical Research

Support for clinical research must include adequate funding for the facilities needed to carry out research including space for clinical inpatient and outpatient research and access to facilities for phenotype analysis, cytogenetic analyses, DNA extraction, and cell cultures.

Proposed Solution

Specialized Research and Diagnostic Centers of Excellence for Rare Diseases should be established on a graduated basis starting with ten regional centers the first year with incremental increases of ten centers per year until 40 research centers of excellence are established.

Suggested Requirements for Each Center

Key Elements of Specialized Research and Diagnostic Centers of Excellence for Rare Diseases Research Program

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17. Small Business Innovative Research/Small Business Technology Transfer (SBIR/STTR) Programs

Recommendation:

The Small Business Innovative Research/Small Business Technology Transfer (SBIR/STTR) Programs are designed to increase small business participation in Federal research and development (R&D) and foster cooperative research efforts between small businesses and research institutions. The research interests of these programs are sufficiently broad to include most rare diseases. It is appropriate that Federal funds for private research serve the best interests of society. This is especially necessary for rare diseases for which the private sector may not be willing to support or capable of supporting research and product development. In the following two programs, specific emphasis should be placed on the need for research of rare diseases.

The "Small Business Research and Development Enhancement Act of 1992" (Public Law 102-564, as amended) requires the agencies of the PHS, DHHS, and certain other Federal agencies to reserve 2.5 percent of their current fiscal year extramural budgets for research or R&D for a SBIR program. In 1998, $265.6 million supported 1,251 SBIR projects. A specified amount of extramural R&D budgets must also be reserved for the STTR program. In 1998, $17.2 million supported 111 STTR projects. It is anticipated that in 1999, NIH will provide approximately $310 million for support of 1,500 SBIR and STTR projects. Separate legislation for both programs is intended to:

Although areas of special programmatic interest or priority may be identified, grant applications are considered in any area within the mission of the participating agencies and awarding components unless otherwise specifically excluded. Small business concerns are encouraged to submit grant applications for proposed research in any program area that falls within the purview of the agencies. Most rare diseases are included in at least one of the NIH program areas.

The NIH and the ORD should develop a program to attract the interest of private industry and solicit applications for the SBIR/STTR programs as a mechanism to stimulate research on rare diseases and the development of products used to prevent, diagnose, and treat rare diseases. The rare diseases represent needy research areas that are too often not emphasized by commercial entities.

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18. Gaining Access to Reliable Information

Recommendation:

The development and accessibility of various databases and information systems have greatly increased the public's ability to obtain information about rare diseases. Many patients with rare diseases or their family members seek information about a particular disorder, ongoing research, research advances, and access to voluntary patient support groups. They conduct much of their information gathering by searching on the Internet or by telephoning NIH ICs. Use of the Internet to obtain information on rare diseases is expected to increase along with public access to the Internet.

The NIH maintains several databases that provide information to health care providers, research investigators, patients, and to the public:

The CRISP system is readily searchable by scientific terms and medical conditions. A summary abstract of each grant or contract proposal funded by the NIH is entered when the award is made. Information contained in the abstract includes the name of the principal investigator, the location of the research institution receiving the award, the NIH IC supporting the research, and other administrative information. CRISP is the only NIH database that includes information from all funded extramural and intramural research programs. The ORD utilizes the CRISP system to identify clinical research studies to be included in the Rare Diseases Clinical Research Database. The ORD should continue to expand the list of rare diseases used as search terms to search the CRISP database and incorporate "rare disease" as a key word and search term.

The information in the CRISP system must be kept current if it is to be of optimal use to patients, family members, health care providers, and other research investigators. Updated abstracts are not prepared on a periodic basis to replace existing but outdated abstracts, making it difficult to determine the status of research projects. For multi-year awards, the research focus may change as research advances occur. Greater effort is required to ensure that databases are kept as current as possible. Additionally, as the NIH continues to make progress on the electronic administration of grant applications, methods should be available for the principal investigator and the sponsoring organization to revise and update directly the summary abstract of the current research. These updates should be completed at least annually. This information would provide the public a better picture of the purpose and status of ongoing research.

Additionally, tremendous strides have been made by both the public and the private sectors to provide information about rare diseases and conditions. Many of these links are prominently displayed on the ORD web site. For example, the National Organization for Rare Disorders (NORD), the Alliance of Genetic Support Groups, the Combined Health Information Database, the Internet version of Medline, PUBMED, and the Online Mendelian Inheritance in Man all provide important information about more rare diseases and conditions. Some of this information is written in technical medical language which is often difficult for the public to understand. However, many of the patient support groups, including NORD and the Genetic Alliance, provide easily readable information to the public. Access to this information should be emphasized and made more readily available. A significant segment of the population does not have access to the Internet, making it crucial that information on rare diseases also be made available through other sources. Patient education programs and toll-free telephone numbers must be developed and utilized to guarantee that the public has access to reliable, up-to-date information. The ORD and the National Human Genome Research Institute plan to develop an Information Center for genetic and rare diseases. This information center will greatly enhance the public's access to information. The Information Center will develop easily understood fact sheets, provide readily available toll-free telephone numbers for patients, family members, researchers, and healthcare providers as well as the general public, and compile timely information tailored to the individual needs of the requestor.

The FDA Modernization Act of 1997 provided a mandate to the Director of NIH to establish and maintain a data bank of information on clinical trials for drugs for serious or life threatening diseases and conditions. The information from these trials are to be disseminated to the public and to health care providers through information and toll-free telephone communications systems. The data bank is to include a registry of clinical trials receiving support from both Federal and private funding sources. Information will be provided on the (1) description of the purpose of each experimental drug; (2) eligibility criteria for participation in the clinical trails; (3) the location of the sites; and (4) a point of contact for those patients wanting to enroll in the clinical study.

The data bank may also contain information pertaining to the results of such treatments, with the consent of the sponsor, including information concerning potential toxicities or adverse effects associated with the use or administration of the experimental treatment. NIH expects to make the database available to the public in 1999.

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19. Gene Vector Development

Recommendation:

There is concern that gene therapy investigators will direct their primary research efforts to those areas of research currently receiving considerable support from the NIH and the private sector. Therefore, the NIH should support research for gene therapy protocols for rare genetic diseases because the private sector is not likely to do so. It is also essential that appropriate research advances in gene therapy from more common disorders be applied to the rare diseases. Likewise, advances on rare genetic diseases will be applicable to the more common diseases. In April of 1999, statistics revealed that of the 248 gene therapy protocols, 173 were for various types of cancer. Only 36 protocols for monogenic disorders were directed towards 14 genetic disorders such as Hemophilia, Fanconi Anemia, and Canavan Disease with 17 of the studies related to research of cystic fibrosis. The opportunities for research advances as a result of gene therapy are endless. The traditional methods of product development must be altered considerably if advances in gene therapy research are to be applied to the thousands of rare genetic disorders. Federal and private sector initiatives should focus on developing gene vectors that will safely and effectively deliver and express the genetic materials. These vectors will serve as the basis for future patient-specific gene therapy of rare diseases.

When disease-specific patient gene therapy research is feasible or planned, research on rare diseases should be included and prominently emphasized. Focused gene therapy research will occur after stable expression of genetic materials is observed. Considerable research efforts are still needed in both basic and clinical research before we arrive at this stage.

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Special Emphasis Panel on the
Coordination of Rare Diseases Research

REFERENCES

  1. The Orphan Drug Act, Public Law 97-414 January 4, 1983.

  2. Health Promotion and Disease Prevention Amendments of 1984, Public Law 98-551, October 30, 1994.

  3. Report of the National Commission on Orphan Diseases, Publication Number HRP-090-7248 United States Government Printing Office, February, 1989.

  4. The NIH Director’s Panel on Clinical Research Report to the Advisory Committee to the NIH Director, December 1997. URL:http://www.nih.gov/news/crp/97report/index.htm

  5. Kelly WN, Randolph, MA, eds. Careers in Clinical Research: Obstacles and Opportunities. Washington DC: National Academy Press; 1994.

  6. Report on Review of Clinical Research in the Center for Scientific Review, National Institutes of Health, June 1998.

  7. Small Business Research and Development Enhancement Act of 1992, Public Law 102-564, as amended October 28, 1992.

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Special Emphasis Panel on the
Coordination of Rare Diseases Research

ROSTER OF PANELISTS

George R. Breese, Ph.D.
Professor, Psychiatry and Pharmacology
University of North Carolina School of Medicine Neurosciences Center
Thurston Bowles Building, CB 7178
Chapel Hill, NC 27599

Marion E. Broome, Ph.D. , R.N.
Professor and Research Chair Nursing of Children
School of Nursing
University of Wisconsin-Milwaukee and the Children's Hospital of Wisconsin
Cunningham Hall, P.O. Box 413
Milwaukee, WI 53021

Paul Citron
Vice President, Science and Technology
Medtronic, Inc.
700 Central Avenue, N.E.
Minneapolis, MN 55432-3576

Edwin H. Cook, Jr., M.D.
Associate Professor, Psychiatry and Pediatrics
Department of Psychiatry, MC 3077
University of Chicago
5841 South Maryland Avenue
Chicago, IL 60637

Gregory A. Curt, M.D.
Clinical Director, National Cancer Institute
National Institutes of Health
Building 10, Room 12N-214, MSC 1904
Bethesda, MD 20892

Mary E. Davidson, M.S.W.
Executive Director
Alliance of Genetic Support Groups
4301 Connecticut Avenue, N.W.
Suite 404
Washington, DC 20008-2304

Clair Francomano, M.D.
Medical Genetics Branch
National Human Genome Research Institute
National Institutes of Health
Building 10, Room 10C101
Bethesda, MD 20892-1852

Alan Goldhammer, Ph.D.
Director of Technical Affairs
Biotechnology Industry Organization
1625 K Street, N.W., Suite 1100
Washington, DC 20006

Marlene E. Haffner, M.D., M.P.H.
Director, Office of Orphan Products Development
Food and Drug Administration
5600 Fishers Lane, Room 8-73, HF-35
Rockville, MD 20857

Ethylin Jabs, M.D.
Director
Center for Craniofacial Development Disorders
Children’s Medical and Surgical Center
Johns Hopkins University School of Medicine
600 North Wolfe Street, Room 10-04
Baltimore, MD 21287-3914

Talmadge E. King, Jr., M.D.
Chief, Medical Services
Department of Medicine
San Francisco General Hospital
University of California, San Francisco
1001 Portrero Avenue, Room 5H22
San Francisco, CA 94110

Marcy E. MacDonald, Ph.D.
Associate Professor of Neurology
Harvard Medical School
Molecular Neurogenetic Unit
Massachusetts General Hospital East
Building 149, Room 6215
13th Street
Charleston, MA 02129

George M. Martin, M.D.
Professor of Pathology
Director, Alzheimer's Disease Research Center
University of WA School of Medicine
Health Sci Bldg. D-509, Box 357470
Seattle, WA 98195

Abbey Meyers
Executive Director
The National Organization for Rare Disorders
P.O. Box 8923
New Fairfield, CT 06812

Alan N. Moshell, M.D.
Director, Skin Diseases Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institutes of Health
Building 45, Room 5AS-25B, MSC 6500
Bethesda, MD 20892-6500

Walter E. Nance, Ph.D., M.D.
Professor and Chair
Department of Human Genetics
Medical College of Virginia
1101 East Marshall Street
Richmond, VA 23219

Elizabeth F. Neufeld, Ph.D.
Professor and Chair
Department of Biological Chemistry
University of CA at Los Angeles
School of Medicine, Box 951737
650 Circle Drive So., Rm. 3-257 CHS
Los Angeles, California 90095-1737

John Opitz, M.D. (Chairperson)
Professor of Pediatrics and Human Genetics
Department of Pediatrics
University of UT School of Medicine
Primary Children's Medical Center
1000 North Medical Drive
Salt Lake City, UT 84113

John Siegfried, M.D.
Pharmaceutical Research and Manufacturers Association
1100 15th Street, N.W.
Washington, DC 20005

Bert Spilker, Ph.D., M.D.
Senior Vice President Scientific and
Regulatory Affairs
Pharmaceutical Research and Manufacturers Association
1100 15th Street, N.W.
Washington, DC 20005

Peter W. Stacpoole, Ph.D., M.D.
Professor of Medicine and Director
General Clinical Research Center
Shands Hospital
University of Florida College of Medicine
Box 100322 JHMHC
Gainesville, FL 32610

Jess Thoene, M.D.
Professor of Pediatrics
University of Michigan School of Medicine
300 North Ingalls Building
Room 1192 Southeast
Ann Arbor, MI 48190-0408

Richard Whitley, M.D.
Professor of Pediatrics, Microbiology and Medicine
University of Alabama at Birmingham
School of Medicine
1600 7th Avenue South, Suite 616
Children's Hospital
Birmingham, AL 35233-0011

National Institutes of Health
Building 31, Room 1B-19, MSC-2084
31 Center Drive
Bethesda, MD 20892-2084
Phone: 301-402-4336
Fax: 301-480-9655
Web Site: http://rarediseases.info.nih.gov/


Last Reviewed: January 27, 2005
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