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Rare Disease Day 2021: FDA Shows Sustained Support of Rare Disease Product Development During the Public Health Emergency

photo collage of rare disease patients and FDA staff who work on rare diseases, with the FDA logo and the words: FDA's Rare Disease Day 2021; March 5, 2021

By: Janet Woodcock, M.D., Acting Commissioner and Janet Maynard, M.D., M.H.S., Director, Office of Orphan Products Development

Rare Disease Day is a time to reflect on both the progress that has been made, and the work that needs to be done, to advance rare disease treatments. The COVID-19 pandemic has added urgency, because people with rare diseases are among the most vulnerable to COVID-19. The U.S. Food and Drug Administration is committed to supporting development of  treatments for rare diseases.  

To recognize Rare Disease Day and engage with the rare disease community, the FDA is holding a virtual public meeting on March 5, 2021. This meeting will bring together stakeholders to highlight strategies that can promote rare disease product development. Additionally, today we are pleased to announce new actions that extend our efforts in this important space:

  • New request for applications (RFA) for the Orphan Products Grants Program for Efficient and Innovative Natural History Studies Addressing Unmet Needs in Rare Diseases. The FDA funds critical rare disease research through a variety of programs, such as the Congressionally-mandated Orphan Products Grants Program. This program has supported rare disease clinical trial research since 1983 and has facilitated over 70 product approvals. In 2020, there were more than five product approvals associated with the Orphan Products Grants program, including a treatment for thyroid eye disease and a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). Both natural history studies and clinical trials for rare diseases are supported through the Orphan Products Grants Program with a goal to increase the number of treatments for rare diseases with an unmet medical need and exert a broad and positive impact on rare disease drug development. The program continues to evolve to address the many unmet needs in rare diseases. This new RFA includes increased emphasis on natural history studies with high quality and interpretable data elements that can facilitate rare disease product development.
  • FDA Rare Disease Photo and Video Project. People are at the heart of the FDA’s work. It is imperative for the voices of patients to be integrated into all phases of medical product development. To build on our many programs and initiatives aimed at promoting inclusion of the patient voice, we captured brief stories from the rare disease community. In addition, the project includes FDA staff as they share examples of rare disease work across the FDA.  
  • Bespoke Gene Therapy Consortium (BGTC). The Center for Biologics Evaluation and Research (CBER) is helping to advance the development of individualized therapies for rare diseases that affect one or a few individuals. Stakeholders recognize the need to have an end-to-end approach for development of individualized (bespoke) gene therapies and sustainable access for patient populations that can benefit from these therapies. CBER is collaborating with the Foundation for the National Institutes of Health (FNIH) and the National Center for Advancing Translational Sciences (NCATS) on development of a ‘Bespoke Gene Therapy Consortium’ (BGTC) to provide a standardized and efficient approach for development and delivery of bespoke AAV-based gene therapies. Efforts include collaborative solutions to address current challenges and regulatory innovations to streamline the development process.

Approvals in 2020 of Novel Drugs and Biologics with Orphan Drug Designation, Treatments for Rare Diseases

As the FDA focuses on the COVID-19 pandemic, the agency also remains dedicated to its crucial role in development of treatments for rare diseases. Patients with rare diseases often have few or no treatment options. In 2020, we continued to see significant progress in the development of treatments for rare diseases, also known as orphan products. Specifically, in 2020, the agency approved 32 novel drugs and biologics with orphan drug designation. In the Center for Drug Evaluation and Research (CDER), 31 of the 53 novel drug approvals, or 58%, were orphan designated products. In CBER, one of the five novel biologic approvals, or 20%, was an orphan designated product and another of these five approvals, although not orphan designated, is for use in a rare disease. 

Janet Woodcock, M.D.
Janet Woodcock, M.D.

Among the many new orphan treatments in 2020, several are particularly noteworthy, including a new drug to treat certain people with Hutchinson-Gilford Progeria Syndrome and progeroid laminopathies, rare conditions caused by certain genetic mutations that lead to premature aging and a new drug to treat patients with hereditary angioedema, a rare disorder characterized by recurrent episodes of severe swelling (angioedema), most commonly in the limbs, face, intestinal tract, and airway. The FDA also approved a CAR T-cell therapy to treat adult patients with relapsed or refractory mantle cell lymphoma, a rare cancer and type of non-Hodgkin lymphoma affecting B-cells, a type of immune cell, in the mantle or outer ring of the lymph node follicles. CAR T-cell therapy involves collecting a patient’s own T-cells, another type of immune cell, and genetically modifying them in the laboratory to fight cancer cells and then infusing them back into the patient. In addition, the FDA approved a treatment to control bleeding episodes occurring in adults and adolescents 12 years of age and older with hemophilia A or B with inhibitors. This is the first product for hemophilia treatment that contains an active ingredient obtained from rabbits genetically engineered to produce a protein necessary for blood coagulation. This approval is an example of our efforts to advance safe biotechnology innovations to support public health. 

In 2020, in order to facilitate, support, and accelerate the development of drugs and therapeutic biologics for rare diseases, CDER’s Office of New Drugs reorganization created a new rare disease hub. This reorganization created the Division of Rare Diseases and Medical Genetics by combining the expertise to evaluate and review marketing applications with certain rare diseases with the Rare Diseases Team to support and coordinate research, collaboration and communication for rare diseases policy and programming.

Development of Medical Devices for Rare Diseases 

In addition to drugs and biologics, we continue to see development of medical devices for rare diseases. Since 1990, the FDA’s Center for Devices and Radiological Health (CDRH) has approved 78 medical devices for orphan indications under the Humanitarian Device Exemption program. The one device from the program approved in 2020 reduces coronary artery atheroma in adult patients with homozygous familial hypercholesterolemia (HOFH) who are either inadequately responsive to or intolerant of maximal therapy for HOFH, including the latest medications and other device therapies approved by the FDA. HOFH is a rare genetic disorder in which individuals developed significantly elevated low-density lipoprotein (LDL) cholesterol or “bad cholesterol” and have an increased risk of early heart disease if not adequately treated. 

Director, Office of Orphan Drugs Development, Janet Maynard, M.D., M.H.S.
Janet Maynard, M.D., M.H.S.

CDRH is continuing important work with stakeholders from across the medical device ecosystem to help better gear medical technology innovation to meet the unique needs of children and small populations. The strategic framework, created by CDRH’s Program for Pediatric and Special Populations and coined ‘SHIP-MD’ (System of Hospitals for Innovation in Pediatrics - Medical Devices), is intended to increase and accelerate medical devices designed, evaluated, and labelled for children and small populations by focusing on leveraging and integrating opportunities across the ecosystem promoting safe technology innovation. Reducing hurdles and aggregating incentives may transform traditional business thinking around investing in the pediatric medical device market. As part of phase 1 of the development plan, all stakeholders interested in pediatric medical device development were invited to participate and provide feedback on the framework during a dynamic three-day virtual public meeting in February, 2021, developed and guided by a multi-stakeholder group. Considerate of stakeholder feedback, a strategic plan for potential continued development of SHIP-MD will be communicated.

Progress in Orphan Drug and Rare Pediatric Disease Designations

2020 was a record-breaking year in terms of the number of orphan drug designation and rare pediatric disease designation requests submitted to the Office of Orphan Products Development. The annual number of orphan drug designation requests has steadily increased from 2012 through 2016 and has remained greater than 500 annually since 2016. In 2020, the Office of Orphan Products Development received 753 new requests for designation, a 41% increase from 2019. Orphan drug designation is an important incentive in rare disease product development and this growth will continue to support development of treatments for rare diseases. Given the ongoing increase in volume and complexity of designations, we continue to enhance and modernize our processes. 

Under our Orphan Drug Modernization Pilot Program we completed our review of 100% of all new orphan drug designation requests within our 90-day goal. Based on the continued volume and increased complexity of orphan drug designation requests, our goal for 2020 was to continue our commitment to quick turnaround and complete at least 90% of all new orphan drug designation requests within a 90-day timeline. We met this goal, with all new orphan drug designation requests reviewed within a 90-day timeline. Moving forward, we will continue to target the same goal as for 2020.  

Orphan Drug and Rare Pediatric Disease Designation Requests Received 2019 vs 2020

Orphan Drug and Rare Pediatric Disease Designation Requests Received 2019 vs 2020

To enhance our processes and workflows, we are strengthening our information technology and automation capabilities through our Orphan Drug Technology Modernization effort. This effort builds on the FDA’s Orphan Drug Modernization Plan and streamlines the orphan drug designation request process by moving from a paper-based process to a new cloud-based online submission portal. The online orphan drug designation submission portal became available in November 2020. The ability to utilize an electronic submission option is especially key during the current public health emergency when the ease of electronic submission options is more important than ever before.  

Similar to the orphan drug designation program, the Rare Pediatric Disease Priority Review Voucher Program and Humanitarian Use Device Program are used to stimulate product development for rare diseases. In 2020, we received a record-breaking number of rare pediatric disease designation requests. Specifically, we received 284 rare pediatric disease designation requests in 2020, a more than 330% increase from 2019. We also received 20 humanitarian use device designation requests, which was similar to the number received in 2019.

Novel Drug and Biological Approvals in 2020 (CBER and CDER)

Novel Drug and Biological Approvals in 2020 (CBER and CDER)

Funding Research to Support Rare Disease Product Development

Research is critical to furthering rare disease product development. The agency continues to provide funding for important research efforts that support various aspects of rare disease product development. For example, CBER awarded a contract to the National Organization of Rare Disorders to design and conduct a pilot rare disease natural history study that might serve as a source of control data for clinical trials of therapies for a rare disease for situations such as when it is not feasible or ethical to enroll and randomize patients to a control arm in a clinical trial. In addition, CDER is continuing important work with the Critical Path Institute building the Rare Disease Cures Accelerator-Data Analytics Platform. The platform will provide an integrated database and analytics hub designed to promote the secure sharing of existing patient-level data and encourage the standardization of new data collection. This data analytics platform will provide a resource through which authorized users can access patient-level clinical data, which may be analyzed to better understand disease progression and the disease heterogeneity across the affected patient population. This in turn can inform trial design, selection of endpoints and other important considerations for drug development.

In 2020, the FDA’s Orphan Products Clinical Trials Grants Program continued to support its approximately 80 ongoing grants and provided funding to support six new clinical trial research grants to principal investigators from academia and industry totaling over $16 million over the next four years. The FDA also provided additional funding to several existing Orphan Products Grants Program grantees to allow ongoing studies to implement necessary steps so their research could continue and ensuring the safety of the study participants during the pandemic. In addition, the FDA is continuing to support five Pediatric Device Consortia grantees to provide advice and support services to innovators of medical devices for children. The program has $6 million in annual funding and received $1 million of additional funding this year, of which $750,000 was allocated to the Pediatric Device Consortia grantees. The funds for the Pediatric Device Consortia grantees will be used to support innovative device solutions to address emerging public health needs for pediatric patients, such as the COVID-19 pandemic.  

The FDA is currently reviewing a second round of grant applications in areas relevant to rare diseases for the Standard Core Clinical Outcome Assessments (COAs) and Related Endpoints Grant Program, the purpose of which is to develop standard core sets of COAs for specific disease indications and have the sets be made publicly available at no cost or minimal cost. 

In addition, as part of the ongoing effort to create a publicly available rare disease COA resource, the Rare Disease Clinical Outcome Assessment Consortium has completed the first phase of a landscape analysis on COAs used to assess aspects of daily function in pediatric populations (i.e., self-care, gross motor function, and fine motor function). Efforts are now underway to perform a gap analysis of existing COAs, and the group is also working on their next landscape review for the domain of communication/language.

Looking forward, despite the tremendous progress in rare disease product development, there is still much work to be done as the vast majority of rare diseases do not have approved treatments. In 2021, we plan to continue and enhance existing rare disease efforts including:

  • Continuation of the Office of Patient Affairs’ Patient Listening Sessions with a rare disease focus to learn more about the experience of having a rare disease or condition directly from patients, caregivers and advocates as well as capturing video testimonials from patient, caregiver and FDA staff about their experience participating in Patient Listening Sessions. 
  • Continuation of an interactive webinar series called “Orphan Grantees Unite” to connect current Orphan Product grantees to advance their shared research goals and further the development of orphan products along the route to marketing approval. Recent sessions have focused on strategies to support rare disease product development during the COVID-19 pandemic. 

The FDA is energized by the progress that has been made. While we recognize there will be challenges, we look forward to continuing our work together with the rare disease community in addressing the significant unmet needs of patients and families living with rare diseases.


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