Zebras Among Us: Advocating for the 30 Million Americans Living with Rare Disease

Abstract

Nearly 30 million (about 1 in 10) Americans have a rare disease. On average, rare disease patients wait 6 years for an accurate and definitive diagnosis and see as many as 12 specialists along their diagnostic journey. In this brief article, we highlight some of what is being done across patient care, medical education, policy, and innovation in order to improve the diagnostic and treatment journeys of rare disease patients. We hope that members of the medical education community will appreciate this call to action and engage in the rare disease space.

Medical school teaches us that when we hear hoofbeats, we should think “horses.” Yet nearly 30 million people in the USA are “zebras” living with a rare disease. There is a 1 in 10 chance of encountering a patient with a rare disease. Despite how common it is to have a rare disease, rare disease patients continue to struggle with prolonged diagnostic journeys, a relative lack of biomedical research compared to more common diseases, and the lack of effective therapies. Physicians, medical students, and other healthcare professionals are likely to encounter rare disease patients at some point in their careers. We are inspired by our experiences at the National Organization for Rare Disorders (NORD) 2022 Rare Diseases and Orphan Products Breakthrough Summit in October 2022 to write a brief article calling the general medical and healthcare community to action around rare disease. We highlight some opportunities for the broader medical community to get involved in rare diseases across patient care, medical education, policy, and innovation. There are many additional avenues in which to improve care for rare disease patients, through fields such as psychiatry and sociology with regard to stressors and the burden of care. Thus, while our discussion does not include every category of opportunity available, we hope to encourage greater discussion and action about rare diseases.

What and Where Is Rare, Exactly?

In the USA, a disease is rare if it affects fewer than 200,000 individuals. This is a definition accepted by the US Food and Drug Administration (FDA) [1]. The National Organization for Rare Disorders (NORD) is one of the largest patient advocacy organizations focused on the identification, treatment, and cure of rare disorders. The National Institutes of Health presently lists more than 7000 rare diseases [2], with some estimates as high as 10,867 [3]; these rare diseases impact nearly every specialty.

The Patient Journey: Unnecessarily Encumbered

Rare disease patients struggle to find advocates in routine care settings. Patients’ diagnostic journeys are often complicated by “the luck of the draw” when trying to find physicians who will listen and exert additional effort to investigate their condition. The average rare disease patient sees up to 12 specialists and waits 6 years before receiving a definitive and accurate diagnosis [4].

Anecdotal evidence from rare disease patients, and data from research, reveals challenges in cultivating a strong physician–patient relationship. According to a rare disease healthcare access survey conducted in 2022 of 1128 patients with rare diseases and their caregivers, 46% of initial providers were unwilling to ask local or regional physicians for help in making a diagnosis [5]. Rare disease patients often have to conduct their own research, bring suspected conditions to physicians for consideration, and build their personal care and advocacy networks.

What about physician willingness to look up potential diseases to see their patients fit the picture? Forty-seven percent of respondents said their initial providers were unwilling to look up suggested diseases [5]. Lack of support and ambiguous patient–physician relationships have left patients and families to become self-reliant. These challenges are compounded when we consider rural communities, communities of poverty, or people of color that may face resource challenges that make it difficult to build personal care and advocacy networks.

We can and must do better. NORD identifies 40 medical institutions as Rare Disease Centers of Excellence. If you see a patient whom you suspect has a rare disease but you are uncertain of how to work up, diagnose, or treat this patient, please visit https://rarediseases.org/centersofexcellence/ and find the nearest Center of Excellence (CoE). Contacting a CoE may dramatically cut down on your patient’s diagnostic journey.

Medical Education: Reforms to Improve Clinical Knowledge and Behavior

In that same rare disease healthcare access survey, 45% of respondents rated their initial providers’ knowledge about rare disease as poor [5]. Physician–patient interactions in the rare disease space are unlike those interactions for more common conditions; patient-directed interaction is very common in the rare disease setting, where the patient acts often as the expert in their condition [6]. Recognizing that exposure through education begins early, several medical schools across the world are reforming curricula to include more rare diseases, with the hopes that future physicians will be more comfortable and able to work with rare disease patients.

Advocacy at our medical schools has led to the inclusion and discussion of rare disease in the preclinical curriculum. In the medical genetics module at Georgetown University School of Medicine (GUSOM), the majority of genetic diseases taught are rare diseases. To address insufficient healthcare provider knowledge about health inequities surrounding rare diseases among healthcare providers and medical educators, GUSOM installed a patient panel session involving patients living with rare genetic disorders, as a part of the medical genetics module. This session was a highlight of the module and left lasting impacts on students, as evidenced by positive course feedback and enthusiastic engagement in raising awareness about rare diseases. We found widespread administrative support, such that in 2023, more rare disease patient panel sessions will be integrated into other modules, including biochemistry.

The patient panels often replace existing curricular elements due to the high density of information in medical education. For example, some team-based learning exercises may be replaced by these patient panels. Schools use different strategies for integrating rare diseases, such as having a patient panel for a certain category of rare diseases (e.g., lipid metabolism disorders); there is no one model that works for all schools or rare conditions. The authors at GUSOM have not received critical voices from faculty or students nor have their faculty mentors. The amount of information presented must be balanced with time and achievability due to the high density of information presented within the medical curriculum.

At the University of Pennsylvania Perelman School of Medicine, rare disease activities can be categorized into three main areas: patient-led events, physician-led events, and researcher-led events. We developed a student-run rare disease elective that incorporates patient-focused sessions aligned with topics covered in the curriculum. For instance, during the gastrointestinal block when students learn about colonoscopies, we held a panel featuring a patient diagnosed with attenuated familial adenomatous polyposis, providing real-life context to enhance the learning experience. Similarly, in the genetics course, built into the curriculum are seven patient case presentations spotlighting individuals living with rare inherited disorders spanning various categories including but not limited to inborn errors of metabolism, mitochondrial disorders, inherited cancer syndromes, connective tissue disorders, and hemoglobinopathies.

In the physician-led events, we explore the possibilities for medical students to make a difference in the field of rare diseases throughout their careers. One of these events, the Medical Genetics Panel, features medical geneticists and other rare disease clinicians and researchers who share their unique career paths and offer guidance on how students can contribute meaningfully to this area of medicine.

Lastly, in our third category of events, we focus on the basic and translational research conducted in the rare disease space. To this end, we invite researchers who discuss their work, delving into the pathophysiology of rare diseases and how their findings can translate into tangible therapeutic advancements at the bedside. An example of this kind of event was a talk by a rheumatologist physician–scientist describing his lab’s investigation of rare rheumatic disorders and the direct impact it had on his patients’ lives.

Throughout our experience, we have consistently observed the profound impact of these events, fostering greater engagement and awareness about rare diseases among our students. Attendance typically ranges from 10 to 20 students per event, and the feedback we receive through post-session surveys is invaluable. Students frequently express their enriched understanding of the challenges faced by patients with rare diseases in clinical practice, as well as the journey they undergo in seeking a diagnosis.

Several of these initiatives at our medical schools started as requests from patients and the rare disease community. We believe that by starting early in education, the next generation of physicians will be able to better listen to, understand, and respond to their future rare disease patients. We encourage readers to learn more about curricular reform efforts and educational resources available at other medical schools and foundations across the globe [7]. A thorough review of curricular reform efforts and educational opportunities is beyond the scope of this article but is always a welcome area of commentary.

Policy and Innovation: Worthwhile Avenues of Advocacy and Research

Opportunities in policy and innovation may appear out of reach to many practicing physicians, medical students, or healthcare professionals. We hope to dispel this myth.

The medical community has been successful in advocating for increased development and access to effective rare disease therapeutics. In 2020, the West Virginia State Medical Association and its coalition partners helped secure passage of legislation that creates a Rare Disease Advisory Council to advise state agencies and legislators in the treatment of rare diseases and to promote the development of and access to effective rare disease treatments. The legislative text is available under West Virginia Code Chapter 16 Public Health, Article 5CC West Virginia Advisory Council on Rare Diseases [8]. Only twenty additional states have similar councils, and additional patient, caregiver, and medical community advocacy is required to expand such councils to more states [9]. Interested individuals can get more involved in advocating for rare disease councils in their states by emailing RDAC@rarediseases.org to get in touch with coordinating efforts at NORD; or they can reach out to other local state advocates such as their state medical associations and allied patient advocacy groups.

At the national level, an American Medical Association Medical Student Section (AMA-MSS) resolution, “Recognizing the Burden of Rare Disease,” is under consideration [10]. Medical student representatives of the AMA-MSS are advocating for a resolution that would, if adopted, compel the AMA to support incentivizing drug companies to develop new therapeutics for rare diseases. The AMA would also support improved diagnostic testing and genomic sequencing to attenuate health disparities in rare diseases. AMA-MSS resolutions have previously made it before the AMA Board of Trustees for potential adoption into official AMA policy and lobbying activities. We encourage practicing physicians and medical students to issue feedback during appropriate times of open comment.

Not to be forgotten, there is significant demand for new treatments in rare diseases. From 2017 to 2021, between 40 and 60% of drug approvals by US FDA’s Center for Drug Evaluation and Research have been for rare or orphan diseases, totaling 126 drugs [11]. The US FDA’s Center for Biologics Evaluation and Research (CBER) approved 25 cellular and gene therapies [12]. Four are gene therapies targeting rare diseases with single-gene disorders/defects. Eighty percent of rare diseases are attributable to a single-gene defect [13]. Still, less than 5% of rare diseases are manageable with approved therapies [14]. Hundreds of investigational new drug applications are before the FDA in just the cell and gene therapy space.

Medical students, practicing academic physicians, and other healthcare professionals may seek to engage in research discovery, obtain scientific or clinical grants, or network through NORD, their nearly 60 student chapters and 40 Centers of Excellence, and/or partner advocacy organizations.

Conclusion

With a 1 in 10 chance of encountering a “zebra” patient with a rare disease, our broader medical community’s discussion around rare diseases must evolve toward understanding how we can better serve the next patient with a rare disease. In our discussion, we have highlighted some opportunities for practicing physicians, medical students, and healthcare professionals to help advocate for rare disease patients.

We recommend that people interested in rare disease advocacy begin by looking for opportunities within local institutions, workplaces, or communities in which they may be involved. These opportunities may be along what we discussed, such as provider education regarding NORD resources and CoEs, or they may be outside of what we discussed. Patients in the community may also be tied into patient groups or organizations that are often condition-specific and may know of opportunities for advocacy; these patient groups may be organized differently, with some being registered 501(c)(3) charity nonprofits and others loosely organized. With the popularity of social media and networking sites, it is easier today than previously to reach out to such groups about opportunities. Finally, NORD is another excellent resource to connect with, and their helpful staff are experienced in networking with volunteers. There are at least 60 student chapters of NORD, which can be found on NORD’s website. These student chapters may additionally serve as community resources for engagement.

We sincerely hope that the broader medical community shares in our enthusiasm for improving care for these deserving patients.

Abbreviations

AMA-MSS

American Medical Association Medical Student Section

CoE

Center of excellence (used in context of NORD)

GUSOM

Georgetown University School of Medicine

NORD

National Organization for Rare Disorders

US FDA

United States Food and Drug Administration

US FDA CBER

US FDA’s Center for Biologics Evaluation and Research

Author Contribution

ELW, YE, WG, and RY made substantial contributions to ideation and the secondary and primary research behind this article. ELW and RY contributed insights from Georgetown, and WG and YE contributed insights from University of Pennsylvania. ELW was a major contributor to writing the manuscript, supported by YE, WG, and RY who contributed specific insights and helped draft and revise the manuscript. All authors approve the submitted version of this article and agree to be personally accountable for their contributions.

Availability of Data and Materials

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Declarations

Ethics Approval and Consent to Participate

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Consent for Publication

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Competing Interests

The authors were recipients of the National Organization for Rare Disorders (NORD) travel/lodging scholarships to attend the NORD 2022 Rare Diseases and Orphan Products Breakthrough Summit. This work is in part inspired by the authors’ experiences at the summit.