Orphan drug approvals by the U.S. Food & Drug Administration (FDA) have increased steadily since 2010. For four of the past five years, they have comprised more than half of all drugs approved per year,. Yet, despite this, only 10 percent of the 7,000 recognized rare diseases have FDA-approved therapies. Consequently, there is relatively little research regarding some 90 percent of rare diseases, which makes it challenging – sometimes exceedingly so – to identify specialists in rare and ultra-rare diseases.
The Center for Drug Evaluation and Research (CDER) at the FDA has several programs to support rare disease drug development. For example, CDER’s Accelerating Rare Disease Cures (ARC) program, launched in 2022, is looking for outcome measures. It is accompanied by the Rare Disease Cures Accelerator – Data and Analytics platform and the Standard Core Clinical Outcome Assessment Grant program. These initiatives are continuing to drive meaningful improvements in approaches to research and, ultimately, therapies and patient outcomes.
Outside the regulatory framework, there is the National Organization for Rare Disorders (NORD) and Rare Diseases Europe (EURODIS) that offer education and resources to support patients and their families that includes links to research groups and medical experts. Disease-specific patient foundations also are invaluable resources.
- 1“New Drug Therapy Approvals 2022,” https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2022, accessed March 20, 2023.
- 2CDER Continues to Make Rare Diseases Priority with Drug Approvals and Programming to Speed Therapeutic Development. http://www.fda.gov/news-events/fda-voices/cder-continues-make-rare-diseases-priority-drug-approvals-and-programming-speed-therapeutic, accessed March 20, 2023.
- 3 “CDER Launches New Accelerating Rare Disease Cures (ARC) Program,” May 10, 2022, https://www.fda.gov/drugs/drug-safety-and-availability/cder-launches-new-accelerating-rare-disease-cures-arc-program
- 4 FDA, “Rare Disease Cures Accelerator,” https://www.fda.gov/drugs/regulatory-science-research-and-education/rare-disease-cures-accelerator, April 21, 2023
- 5 U.S. FDA, “New Funding Opportunity: FDA Standard Core Clinical Outcome Assessments (COA) and Endpoints Pilot Grant Program,” https://www.fda.gov/drugs/news-events-human-drugs/new-funding-opportunity-fda-standard-core-clinical-outcome-assessments-coas-and-endpoints-pilot, Accessed April 21, 2023.
- 6 National Organization for Rare Disorders (NORD), https://rarediseases.org/, Accessed April 21, 2023.
- 7 EURODIS, “Projects & Services.” https://eurodis.com/products-services, Acessed April 21, 2023.
All combined, however, these resources still only address a small fraction of the needs and involve merely a subset of all those clinicians who have rare disease knowledge.
Rare Disease Education is Inadequate
There has been a tremendous evolution, not only in medicine, but in reach, as determined by access to, and equity around, healthcare, as well as awareness regarding the role of demographics such as age, class, ethnicity and geographic location.
While those factors are each important in diagnosing and treating more prevalent diseases such as diabetes and heart disease, they become even more important when rare diseases are involved. For more prevalent diseases, for instance, we can look at subsets of populations and access claims data from large, comprehensive databases. In rare diseases, however, enough data may not be readily available, whether it is fundamentally lacking quantitatively because of the complexity of the disease or is misrepresented because of misdiagnoses or lack of diagnostic information.
For those situations, even obtaining an accurate diagnosis, developing an effective treatment plan and identifying health care providers can be fraught with difficulties. Such differences set rare diseases apart from mainstream therapeutic areas and, because they affect pharma’s ability to engage with rare disease experts, exacerbate the process of identifying and engaging the right clinicians.
Product development for rare diseases is complicated by multiple factors, including the scarcity of well-defined meaningful outcome measures and reliable natural history of disease data, much of which resides in data silos. Consequently, the patient journey is convoluted and, in 2013, required an average of seven years to achieve an accurate diagnosis. More recently, a 2022 Spanish study of 3,304 individuals with rare disease found the mean time to accurately diagnose their conditions exceeded six years. Another Spanish study found that receiving an accurate diagnosis typically involved more than 10 specialists and often required the patient to travel to another region for care.
For patients and their families, the diagnostic odyssey also is beset by psychological and financial hardships. During their journey, patients invariably endure a long parade of physicians, potentially mistaken diagnoses, inappropriate treatments and medical
- 8Denton N, Molloy M, Charleston S, et al, “Data Silos are Undermining Drug Development and Failing Rare Disease Patients,” Orphanet J Rare Dis. 2021 Apr 7;16(1):161, doi: 10.1186/s13023-021-01806-4
- 9 National Organization for Rare Disorders (NORD), “30 Years After the Orphan Drug Act: It Still Takes Too Long for People with Rare Diseases to Get an Accurate Diagnosis,” https://rarediseases.org/30-years-after-the-orphan-drug-act-it-still-takes-too-long-for-people-with-rare-diseases-to-get-an-accurate-diagnosis/ October 23, 2013, Accessed April 21, 2023.
- 10Benito-Lozano J, Lopez-Villalba B, Arias-Merino G, et al, “Diagnostic Delay in Rare Diseases: Data from the Spanish Rare Diseases Patient Registry,” Orphanet J Rare Dis., 2022 Nov 17;17(1):418, doi: 10.1186/s13023-022-02530-3
- 11 Benitoi-Lozano J, Arias-Merino G, Gomez-Martinez M, et al, “Diagnostic Process in Rare Diseases: Determinants Associated with Diagnostic Delay,” Int J Environ Res Public Health. 2022 May 26;19(11):6456, doi: 10.3390/ijerph19116456.
complications before the condition is correctly identified. In the past decade, there have been more than 300 citations discussing misdiagnosis of rare diseases in the United States.
The most significant complication is premature death. Unfortunately, approximately 30 percent of children with rare diseases die by the age of five years. Many, therefore, are never diagnosed accurately and in some cases, misdiagnosis led to treatments that exacerbated their conditions.
Multiple studies have documented the correlation between delayed diagnoses and increases in healthcare costs. For example, one study of functional neurological disorder (FND), which, although not a rare disease, is frequently misdiagnosed, showed prediagnostic costs for FND were nearly three times higher than for those diagnosed with other neurological disorders. Those diagnoses took 48 months, versus the median of 12 months for other neurological disorders.
The diagnosis of neuromyelitis optica spectrum disorder (NMOSD) offers another example. NMOSD is a rare autoimmune disease characterized by inflammatory attacks on the central nervous system that lead to permanent neurological damage. A review of five years of records involving 10,697 patients who had or probably had NMOSD were compared to an equal number of controls. The researchers found that patients with NMOSD were more likely to be diagnosed as having conditions with similar manifestations (42% of NMOSD patients vs 31% of controls), and that they were significantly more likely to be prescribed medications known to exacerbate NMOSD.
The effects on the families of undiagnosed patients – especially children – are significant, too, and manifest as high anxiety and depression.
The difficulty of diagnosing rare diseases stems not only from the rarity of the diseases, but also from the dearth of information on the diseases and within the medical profession. A survey of 927 physicians in 16 therapeutic specialties in the U.S. and Europe found that 70 percent believed rare diseases were 10- to 100-fold rarer than
- 12 “Rare Childhood Diseases,” National Stem Cell Foundation, https://nationalstemcellfoundation.org/focus/rare-childhood-diseases/#:~:text=30%25%20of%20children%20with%20rare%20disease%20will%20not,of%20deaths%20in%20the%20first%20year%20of%20life, Accessed April 21, 2023.
- 13 Cuoco S., Scannapieco S, Carotenuto I, et al. “Higher Health Service Costs Associated with Delayed Diagnosis of Functional Neurological Disorder,” J Neuropsychiatry Clin Neurosci. 2023 Winter;35(1):86-91. doi: 10.1176/appi.neuropsych.21110288. Epub 2022 Aug 22.
- 14Foley D, Polson M, Williams T., “Misdiagnosis and Disease-Exacerbating Medication Use in Patients with Neuromyelitis Optica Spectrum Disorder in the United States: A Retrospective Claims Analysis,” Presented at: Nexus Meeting of the Academy of Managed Care Pharmacy. 2022
- 15McConkie-Rosell A, Hooper SR, Pena LDM, et al, “Psychosocial Profiles of Parents of Children with Undiagnosed Diseases: Managing Well or Just Managing?” J Genet Counsel, January 2, 2018, https://doi.org/10.1007/s10897-017-0193-5.
they actually are. In that same survey, nearly 90 percent said they have been involved in diagnosing a rare disease, but only 20 percent said they were confident in making those diagnoses.
Collectively, these studies underscore the fact that physician education regarding rare diseases is incredibly important. There are other lessons, too, for the greater healthcare system.
When that study focused on answers from the 60 nephrologists who responded, the authors found that 70 percent of the American respondents – but only 43 percent of European respondents – cited a lack of knowledge regarding the signs and symptoms of rare diseases. Access to appropriate diagnostic tests was a challenge for 57 percent of American respondents and 37 percent of Europeans.
That particular study didn’t delve into why physicians indicated access to diagnostic tests was challenging. Other studies, however, have explored that landscape. For many rare diseases, tests have not yet been developed, although gene and exome sequencing and the use of microarray assays have enabled diagnoses for between 25 and 35 percent of otherwise undiagnosed patients. Even when appropriate tests exist, however, such as whole exome sequencing, their availability often is restricted because of conflicting or unavailable evidence regarding clinical utility and cost effectiveness. In other cases, access is constrained the availability of reference laboratories able to perform (and be reimbursed for) the tests.
Such studies suggest that improving the patient odyssey through rare disease diagnosis and treatment, therefore, requires great collaboration among governments (to establish policy), physicians, scientists, drug developers, patients and patient advocates.
Identifying Rare Disease Experts is Particularly Challenging
Identifying physicians with expertise in specific rare diseases can be difficult.
Consequently, if physicians have difficulty identifying the disease, it is understandable that Medical Affairs (MA) professionals also will have difficulty identifying the treating physicians. This is why engagement is different for pharmaceutical companies that are developing medicines for rare diseases.
- 16Rohani-Montez C. “MO035: Education Needs in Diagnosing Rare Renal Disease: A Clinician Survey,” Nephrology Dialysis Transplantation, May 3, 2022, https://academic.oup.com/ndt/article/37/Supplement_3/gfac062.016/6578382, accessed March 20, 2023.
- 17 Marwaha S, Knowles JW, Ashley EA, “A Guide for the Diagnosis of Rare and Undiagnosed Disease: Beyond the Exome,” Genome Med., 2022 Feb 28;14(1):23. doi: 10.1186/s13073-022-01026-w.
- 18Hayeems RZ, Bernier F, Boycott KM, et al, “Positioning Whole Exome Sequencing in the Diagnostic Pathway for Rare Disease to Optimise Utility: A Protocol for an Observational Cohort Study and an Economic Evaluation,” 2022 Oct 10;12(10):e061468, doi: 10.1136/bmjopen-2022-061468
- 19Vandevelde NM, Vermeersch P, Devreese KMJ, et al, “Belgian Rare Diseases Plan in Clinical Pathology: Identification of Key Biochemical Diagnostic Tests and Establishment of Reference Laboratories and Financing Conditions,” Orphanet J Rare Dis. 2021 Feb 17;16(1):89. doi: 10.1186/s13023-021-01728-1
Consider the hypothetical case of AA who, as a child, experienced pains in his hands and feet and intolerance to heat and cold. This impaired his ability to play sports. He was seen by a pediatrician, but did not receive a diagnosis.
During adolescence, he continued to experience fatigue and gastrointestinal distress. It wasn’t until his forties, when he had a stroke and experienced significant reduction in kidney function, that he was referred to a nephrologist. That physician had treated other patients with Fabry disease and recognized those symptoms in AA, who then was diagnosed with that disease. Over the years, AA’s Fabry disease had progressed significantly, impacting quality of life and causing a plethora of visits to different specialties, which is often the case with rare diseases.
This case highlights the fact that patients will present to various specialties. It is imperative, therefore, to engage with clinicians beyond the key treaters and treatment centers, recognizing the many additional touchpoints and specialties in the patient’s odyssey. In doing so, Medical Affairs can develop a more robust perspective as it engages those specialties as part of its stakeholder identification, engagement and strategic planning initiatives.
New Ways To Diagnose Rare Diseases Are On The Horizon
Artificial intelligence combined with machine learning is beginning to be used to identify misdiagnosed or undiagnosed patients early in their diagnostic odyssey, but it isn’t perfect.
By combing the electronic health records (EHRs), the goal is to drive as much relevant information as possible to the machine learning algorithms so that rare diseases may be detected that otherwise may not be suspected. As yet, however, precise predictive modeling is impossible because of the limited quantity of data available to train the application. That said, AI still is useful in combing through EHRs to identify any red flags that may prompt a physician to consider the possibility of a rare disease and to perform additional tests. IQVIA scientists are taking this further by integrating AI into solutions that combine analytics, technology and data, thereby helping scientists explore further, faster and more accurately.
To Help, Engage the Right Experts
What MA professionals can do while waiting for AI and machine learning to mature is to widen the field of physicians who may be treating patients and/or have relevant expertise with rare diseases, and thereby enhance engagement.
MA professionals, particularly Medical Science Liaisons, can make a huge difference in the lives of many patients with rare diseases by putting information into the hands of clinicians who have the potential to shorten the diagnostic odyssey. Therefore, it is MA’s
- 20 Wany Y, Mack C, Zhang F, Cai Y, et al. Detecting Rare Diseases: A Case Study Using Machine Learning Semi-Supervised Network to Identify Under-Diagnosed Patients. Presented at 35th Annual International Conference on Pharmacoepidemiology and Therapeutic Risk Management. International Society for Pharmacoepidemiology, 2019.
duty to find and engage these experts, informing them of emerging scientific developments, potential treatments and clinical trials. Otherwise, MA may be missing a huge opportunity to shorten the diagnostic odyssey and improve patient outcomes.
Taking both a targeted and differential approach to identify experts expands the pool beyond traditional KOLs. This comprehensive strategy employs a peripheral approach grounded in scientific evidence, analogous diseases and differential diagnosis, as well as traditional methods to identify specialists. The result is a pool of traditional and non-traditional clinicians with whom to share information. Ultimately, combining peripheral and traditional identification methods has the potential to improve outcomes for patients with rare diseases.
Angelman syndrome is a good example. This genetic disorder affects 15,000 people in the U.S., and approximately a half million people worldwide. Patients suffer developmental and neurological abnormalities that appear illogical upon examination.
The traditional approach to identifying experts in this area concentrates on neurology and focuses on centers of excellence and known specialists. To look further, we first must ensure our data lake is complete. This means looking first at scientific evidence regarding Angelman syndrome from sources such as PubMed, conference data and clinical trials.
From that point, we should look beyond Angelman’s syndrome to analogous diseases – those which may appear in the differential diagnosis for Angelman or present with similar symptoms. We also should look at the various sequelae associated with the rare disease, how those sequelae might be managed and by which specialties, thus potentially broadening the scope of clinicians who also may encounter such patients.
Then we can begin to identify individuals based on the literature who have expertise in Angelman’s disease. By reviewing their entire body of work, certain themes may emerge that can be used to create a specific search strategy.
For example, the primary search term might be “Angelman’s syndrome,” followed by specific analogous diseases the literature search revealed. This can be accomplished by identifying clinicians with research in Angelman’s and then finding additional “non-Angelman’s” work they’ve created within the scope of their experience. For Angelman’s syndrome, this might include autism spectrum, cerebral palsy, Rett syndrome, Mowat-Wilson Syndrome, and several other conditions. That approach reveals many-fold more potentially relevant abstracts, and thus, many more potential clinicians who may have the medical experience to recognize and treat Angelman’s. Based upon their foundation of knowledge about analogous conditions, these clinicians may, therefore, be open to discussions about new treatments, thus broadening our scope of engagement.
Expanding the Approach to Rare Disease Expert Engagement
To Paraphrase “the Great One, Wayne Gretsky,” this approach helps MAs “skate to where the puck will be, rather than where it has been.”
This expands your reach and your ability to engage these clinicians based upon their needs and interests, enabling Medical Affairs professionals to identify clinicians best able to use specific information about new and emerging therapeutics and clinical trials. This approach builds awareness in a way that, hopefully, helps physicians make more accurate diagnoses earlier.
This approach enables Medical Affairs to reach out to physicians who probably treat the disease areas of interest. To paraphrase a quote from “The Great One,” Wayne Gretsky, this approach helps MAs “skate to where the puck will be, rather than where it has been.”
In that way, as clinicians in industry, we can make a huge difference in the lives of many patients with rare diseases by assuring information about new, innovative treatments is in the hands of those who may have the potential to shorten the diagnostic odyssey for those in need.
“As clinicians in industry, we can make a huge difference in the lives of many patients with rare diseases by assuring information about new, innovative treatments is in the hands of those who may have the potential to shorten the diagnostic odyssey for those in need.”
Joseph B. Laudano, BS Pharm, PharmD
Joseph B. Laudano, is Vice President, Medical Affairs at Pharmaspectra LLC. Dr. Laudano has over 30 years of experience in the pharmaceutical industry. Before joining Pharmaspectra, he was Vice President of Medical Affairs at Alliqua Biomedical. Before joining Alliqua Biomedical, he was Senior Director of Medical Affairs and head of Publication Planning at Forest Research Institute. Prior to this, he spent 21 years at Roche Laboratories U.S. in Medical Affairs and Marketing in various roles including; Director of Medical Information, Product Director, and Medical Science Liaison. He was Roche’s first Medical Science Liaison, covering major institutions for the whole country and paved the way for the creation of an entire team. Joe has extensive research experience in several different therapeutic areas including infectious diseases, dermatology, and oncology, and has authored numerous publications and scientific posters.
Nikky Oladunmoye, PharmD, MPH
Nikky Oladunmoye is a pharmacist with a background in Public Health. She has 15 years of pharmaceutical industry experience within Medical Affairs and Regulatory Strategy. She currently works in Rare Disease at Pfizer Canada ULC as a Medical Affairs Scientist in Rare Hematology and Rare Neurology. Her industry experience spans internal medicine, neuroscience, oncology; and she finds working in rare disease incredibly rewarding due to the significant unmet need and the opportunity for life changing therapies.
Gail Dutton, BS
Gail Dutton has covered the business of life science for more than three decades, writing about the evolution of biotechnology, management trends, human resources development, and related topics. Her writing has appeared in more than 45 print and online publications, including Genetic Engineering News, BioSpace, and Life Science Leader. She has presented to the National Defense University and the Genopole Paris conference and is particularly interested in new technologies driving innovation throughout the enterprise.
David Kelaher, BPharm, MSc
David Kelaher is Chief Medical Officer at Pharmaspectra. David has 20 years of experience in pharmaceutical Medical Affairs and healthcare communications, driving therapeutic portfolio success and international brand growth for several of the world’s leading companies, such as Sanofi, Abbvie, and AstraZeneca.
He was previously Managing Director of BBH Health, a specialist strategic and creative business within BBH, one of the world’s most awarded agencies. During his five years at the agency, BBH Health became a global agency of record for HUMIRA, Symbicort, and Brilinta, and led the global brand development and launch campaigns for Fasenra, Skyrizi, and Rinvoq. Prior to this, David spent a decade at Sanofi, including Medical Affairs roles in the Australian affiliate, and as a Global Medical Director in the company’s Paris headquarters.