May you briefly introduce yourself to our readers?
Hanns Lochmüller (HL): I am trained as a neurologist and see patients with muscle disorders in my clinic. For the last 20 years, I have been involved with research into the causes of and therapeutic approaches for muscle disorders. I am currently Professor of Experimental Myology at the Institute of Genetic Medicine, Newcastle University (UK). Several of my functions relate to my work with rare disorders: I am scientific coordinator of EuroBioBank, chair of the executive committee of TREAT-NMD, and chair of the interdisciplinary scientific committee of IRDiRC, and coordinator of RD-Connect, a new European project creating an integrated platform for rare disease research.
Stephen Groft (SG): My current position is the Director, Office of Rare Diseases Research (ORDR) in the National Center for Advancing Translational Sciences (NCATS) at the USA National Institutes of Health (NCATS). The goal of ORDR is to generate research activities in rare diseases research. My professional experiences in orphan products development and rare diseases research started in 1982 with the establishment of the FDA’s Office of Orphan Products Development where I had review responsibility for identifying potential orphan products for neurologic and psychiatric disorders. My undergraduate and graduate training was in Pharmacy and I realized in the early 1960’s the lack of adequate treatments for most disorders, especially those conditions with relatively small populations and for those conditions with very little available information beyond a description of the disease and expected outcomes. I also had the opportunity to be the Executive Director of the National Commission on Orphan Diseases from 1987-1989 in the Office of the Assistant Secretary for Health at the Department of the Health and Human Services. The Commission was charged to review activities after the implementation of the Orphan Drug Act in 1983 and to offer recommendations for a future direction for orphan products development and rare diseases research. In 1998, NIH initiated a Special Emphasis Panel on the Coordination of Rare Diseases Research. The goals included the task of developing strategies to foster a better coordination of research and development activities. Reports from these advisory groups are available on the ORDR website.
Yukiko Nishimura (YN): My name is Yukiko Nishimura, Assistant Professor of Department of Intellectual Property and Social Application of Technology, Research Center for Advanced Science and Technology at The University of Tokyo, Visiting Lecturer of Institute for Integrated Cell-Material Sciences at Kyoto University, and Board Member of NPO Promotion Research for Intellectual Property (PRIP Tokyo). I have been working for Japan Patient Association, the biggest association related to NANBYO in Japan as a Chief of International Relations (NANBYO is a Japanese word for rare and intractable diseases). I have more than 9 years of university and 4 years of ministry working experiences and 8 years of administrative experience of NPO. I have conducted several research areas: technology transfer, intellectual property management, human resource development of IP/TT area, innovation management, and social application of technology. My targeting area is not only a single but also very interdisciplinary, and I have constructed unique and varied networks related to these area in the whole of Japan and Asian countries.
First of all, is there a particular reason for you to be involved in rare diseases activities? When did you first “face” the rare diseases?
HL: Most muscle disorders and many neurological conditions are rare disorders. Therefore, they have played a major part throughout my professional life. Many of them have a genetic basis which has been elucidated through advances in genetic and genomic research. Because of their rarity, they share similar challenges with other rare disorders from different fields of medicine.
SG: The absence of available diagnostics and treatments for most diseases has been a personal concern of mine for many years. The clinical outcomes of treatment with a new product can be immediately observable and dramatic for patients. The successful development of a new product requires overcoming the challenges of conducting research and developing compounds to meet the needs of the rare diseases community consisting of patients and their families, patient advocacy groups, and philanthropic foundations, healthcare providers, research investigators, the pharmaceutical, biotechnology and medical devices industry, and government research, regulatory, reimbursement agencies. Identifying resources that could be utilized by the rare diseases community is the key to collaborative efforts required for research and development activities for rare diseases and orphan products. Meeting these needs has resulted in professional and personal commitments that have guided me for most of my career.
As a child growing up in a small town and knowing most people, there was an awareness of those who had uncommon diseases with many special and unmet needs. Cystic fibrosis, childhood leukemia, brain tumors, Marfan syndrome, Polio, cerebral palsy, Parkinson’s disease, and Multiple Sclerosis were a few of the diseases that I encountered very early in my life. I sensed that at some time in the future, I would have some involvement with patients and families with these diseases. When Dr. Marion Finkel, the first Director of the Office of Orphan Products Development at FDA, asked me to join the new office in 1982, it was an easy decision to join the very small initiative with an unknown and uncertain future.
YN: In 2004, Japanese Pharmaceutical Affairs Law has been revised, and then I found Japanese orphan drug market would be created in this revision. At that time, my main research area was making startups and technology transfer and I would like to attract talented researchers to rare disease research area for the orphan drug development. We gathered basic researchers who were interested in rare disease area and built a network. We had held regular workshops, however, we realized we need much further information from patients’ side and also the world. Many of us are basic researchers, and we have no chance to hear from patient voice. We have attended the International Conference on Rare Diseases (ICORD) since 2008, and also started to contact to patient organizations. I never forget to participate in the patient meeting for the first time. Our active period is only about 5 years. However, we have now strong relationships with Japan Patients Association, other patient groups on a global scale, universities, hospitals, pharmaceutical companies (including from mega pharmaceutical to biotech startups) and their associations, and Japanese ministries (Ministry of Health, Economy, and Education) based on the relations of trust. We have published over 20 papers in this field, and several policy recommendations to Ministries. We hope to make a “Hub” for orphan drug development promotion and to build a portal of this area to the world from Japan.
What’s your explanation of the growing interest in rare diseases topics?
HL: There are numerous possible explanations. Through better and faster ways of communication, patients with rare diseases can connect much better with other patients affected by the same condition and have successfully come together in patient organisations and lobbied for recognition. Politicians, industry and the health care sector have recognized that rare diseases collectively are a major cause of morbidity and disability. Scientists may see rare diseases as a test case for molecular discoveries and for developing innovative treatments, and pharmaceutical companies believe there may be a market for rare diseases therapies as opposed to another new “blockbuster” for common diseases.
SG: There are numerous reasons for the expanding interest in rare diseases research and orphan products development activities in a growing number of countries and this increase has resulted in a global interest. There is an increased understanding that rare diseases are a global public health problem due to the lack of appropriate treatments. Patients and families understand that public awareness and knowledge of their diseases are necessities and this requires participation in the establishment and the activities of patient advocacy groups. Their outreach activities may require personal availability to the public and to the media. As we expand our knowledge of rare diseases and with greater access to patients willing to participate in clinical studies and trials, increased scientific opportunities exist for the research communities. Certainly, increased research budgets of the past 10-15 years have enabled more investigators and especially new and younger investigators to develop a research emphasis on rare diseases. The increase in research interest has led to the discovery of potential new products and increased interactions and licensing agreements with the pharmaceutical industry which may lead to commercialization of these discoveries and newer technologies. There continues to be a growing interest in smaller rare diseases niche markets by the pharmaceutical, biological, and medical device industries. Due to the lack of a large number of patients with rare diseases at any one location, multiple research sites are required for successful completion of clinical studies. An increased number of research investigators, understand how to design and conduct multi-center, international clinical trials of rare diseases and condition with smaller patient populations available for participation. This knowledge must be exported to those considering such studies.
YN: As I described before, my main research area is Social Science. Therefore, I would like to try to bridge among related people and society. I am interested in: 1) collaboration among the appropriate stakeholders in an attempt to speed up the development of new rare diseases treatments and orphan drugs/products; 2) making proposal to national/regional government some concrete plan for this area; 3) practising several workshop and awareness campaign with patient groups; 4) establishing an international communication network with patient groups and providing/exchanging valuable information. I also have conducted the investment activity with professionals for seeking alternative ways to accelerate developments and commercialization of new therapies for rare diseases. Our first target is one of mitochondrial disease.
There are numerous and very different rare diseases issues. Which of them should be globally addressed and which ones should be managed at national/regional level?
HL: Research, especially clinical trials, requires international collaboration. Patient care needs to be organized and accessible at a national or regional level, but it is still important to pay attention to best practice care standards agreed at an international level.
SG: Rare diseases do not recognize global, national, or regional boundaries. With encouragement and opportunities made available at the local, regional or national levels, stronger individual and national program emphases will lead to expanded global approaches. As planning activities and discussions are held for new projects and programs, the rare diseases community should ask how any activity can be made available for patients throughout the world. Personnel and financial resources may be available from national sources to enable the participation of their citizens in the development and access as participants to collaborative clinical research studies and clinical trials, natural history studies, patient registries, collection and distribution of biospecimen samples from patients and family members. There is also increased national and international interest and support for the development of more directed translational research activities leading to the development of interventions and diagnostics. Public-private partnerships will require the utilization of the strengths and resources of the research partners involved in the development activities for rare diseases and orphan products.
YN: At first, Japanese government should carry out effective measures related to NANBYO area. Japan has a long history of measures for NANBYO, which now requires a review. We should reconsider the meaning of “NANBYO”, intended diseases in “NANBYO”, and equitable support for all “NANBYO”. We also have to discuss how to facilitate interactions among other related policies (ex. Common healthcare system, Act on Welfare of Physically Disabled Persons, etc). Besides that, we need the review of orphan drug development supporting system, information sharing/providing among stakeholders, human resource development related to this field.
In your opinion, what the global approach to rare diseases should consist of?
HL: In general, international research collaborations in rare diseases are important to develop new and better diagnosis and treatments. This has been recognized by major institutions and funders like the European Commission and the NIH resulting in a truly global initiative called IRDiRC. The goals of IRDiRC are to diagnose all rare diseases and to develop 200 new therapies by the year 2020. This globally harmonised approach to research funding should help reduce duplication of effort and accelerate research developments. In parallel, policy initiatives such as national plans for rare diseases should provide an impetus for all countries.
SG: Shared programs with potential partners have proven to be a successful approach to rare diseases on a global basis. We must utilize the proven models for product discovery and development. These models require repurposing of approved and investigational products and establishing working relationships with the staff of regulatory agencies and our industry partners. We see the value of multidisciplinary collaborative research efforts involving research consortia and networks to attain the critical mass of investigators and patients required to increase the likelihood of completing the research projects in a timely fashion. Disease-specific patient advocacy groups have also proven to be reliable research partners and can assist in patient recruitment for clinical trials and linking patients from around the world through their organization. We have the capability of linking the community together electronically and need to consider the strategic alliances required for rare diseases research advances and orphan product development activities. We also are seeing more preclinical and clinical translational research resources becoming available from funding sources such as the NIH in the USA. We have to develop an awareness of these resources and availability for innovative research projects in rare diseases.
YN: It is essential that patient groups adopt a global approach to memberships and activities in order to provide better access to information and interventions to improve quality of life for all patients with rare diseases. Almost all global projects are established under the initiative of the government, however, we should discuss on global level how to provide unbiased information to patients whose home governments don’t participate in. As Japanese government, we have to select a person in a position of responsibility as participant in those meetings, and he/she makes efforts to convey to our rich information actively.
Recently, many international projects and consortia have focused on managing undiagnosed cases and developing new therapies. What are the perspectives of these activities?
HL: The –omics revolution will hopefully accelerate therapeutic developments in rare diseases, and international coordination and collaboration through projects and consortia such as IRDiRC are essential to success, as resources are limited. In the long-term, it will be important to make the rare diseases field more attractive to young clinicians and scientists, and to reward collaboration.
SG: The difficulty of obtaining the appropriate diagnosis has resulted in a diagnostic odyssey for many patients. Surveys have shown that nearly 15% of patients have waited for over 5 years to obtain the correct diagnosis. We think diagnostic capabilities will continue to improve, particularly for rare genetic disorders. As we gain additional experience and knowledge, the promise exists for quicker and more accurate diagnoses resulting from interpreting the results of whole genome sequencing for individuals. Costs continue to drop for these tests. A major need is to assure an adequate number of clinicians are available and trained appropriately to interpret the results. It is important for these clinicians to communicate the results back to patients and their families.
We recognize that the immediate goal of most patients is to obtain the diagnosis. It is reassuring to patients and families to have the correct diagnosis regardless if an intervention is available or not. Having the diagnosis enables individuals to expand their knowledgebase about their disease. They will attempt to learn as much as possible about their disease from numerous sources. They will attempt to locate others with the same or related diseases, including established patient advocacy groups, and will seek out those clinicians with a better understanding of their disease or who have established standards of care for their disease.
One of the many benefits of research networks and consortia is the ability to aggregate clinical data from a large number of patients from multiple research sites throughout the world. Utilizing a global approach, patient registries, collection of bio-specimen samples and longitudinal and natural history studies can be opened and prepare the way for clinical trials when interventions become available for evaluation.
YN: These activities are very valuable. Japan country has to participate in, but at the same time, we have to discuss several issues as follows: 1) Defining undiagnosed diseases as a brand new type or a subtype of an existing rare disease to re-build the concept of certain diseases along with constructing a better information system, 2) Coordinating national centers, hospitals, and university hospitals so that patients can be registered and experts can evaluate them with ease, 3) Treatment development for NANBYO diseases needs an effective registry system of patients and patients’ lead research bringing global collaboration into view.
What’s your message to “Rare Diseases & Orphan Drugs” readers?
HL: We are grateful for the support of many people in the RD field, but particular patients and families affected by RD. We encourage patients and families to get involved with efforts such as patient registries that may be available for their disease.
SG: Success is defined as the development of appropriate diagnostics and access to new interventions. For most rare diseases, there are no appropriate treatments available and this measure of success may have to be considered until such time as a treatment becomes available. The recent increased emphasis on translational research programs offers tremendous hope that initiatives will speed up the development of interventions. These interventions may come from new compounds or discoveries of new treatments from the repurposing of products already approved and available for use in other rare diseases. Translational research enables discoveries from industry and academic research centers, government laboratories and clinics, and foundations to be “translated” into interventions. To address this issue, several patients and patient advocacy groups have developed model systems to speed up the development of products for their disease. This model requires careful planning of global research initiatives and attention to the details of the types of preclinical and studies in humans required by regulatory agencies, the resources (funds and personnel) required to conduct these studies. A novel approach just announced by NIH with several grant awards will look to the identification of safer and more useful products by the use of tissue chip technology to speed up the development of potential compounds with an acceptable safety profile.
Since resources will be required from various sources, it is important to develop collaborative partnerships based on trust and commitment to develop diagnostics and treatments. This shared trust is built upon personal collaboration established with continued communication among all partners. Strong leadership at the patient advocacy group level is the defining factor in the successful approaches to rare diseases research and orphan products development. We are unable to meet the treatment needs for everyone with a specific rare disease but with technology available today, it is essential that the rare diseases community – patients, families, patient advocacy groups, researchers, research and regulatory agencies, and industry partners – maintain constant contact. Partnerships can assist in developing the very best information about a disease, establishing standards of care, how best to live and cope with a rare disease throughout their lifetime. Continued support for the leadership of PAGs is essential to encourage the development of information to inform clinicians, legislative bodies in individual countries, and the media and the public. Support for these activities that can be initiated at local, regional, national, and global levels is essential. We come full circle starting with patients in need of diagnostics and treatments and ending with patients who have been active participants and the leaders to accomplish these goals. Patients and their families will touch all partners in the rare diseases community dedicated to developing these interventions. Our task is to remove the barriers and facilitate the steps for the rare disease community to move forward as quickly as possible.
YN: I am sure that I don’t have rich empirical value of these fields. However, I have many talented people behind me and a strong network. I strongly believe all of them support to our activities, because they also need them. My standing point is very unique, but I believe strongly in the value of my type, as a spokesman to the society. My message is very simple: Connection + Collaboration = Creation! We can connect with, collaborate with, and then, create something valuable for the society. I would like to connect with your “wish to connect”.