By Maxine Bookbinder

March 8, 2016 | Rare Disease Day has gained recognition, research, and funding since its inception in Europe on February 29, 2008. Now observed globally, Rare Disease Day aims to increase awareness of rare diseases and their impact on patients, families, and medical professionals, hundreds of organizations are helping doctors find diagnoses and sufferers find solace. But, for a majority of the 350 million rare disease victims worldwide, hope is elusive and cures are as rare as the illnesses from which they suffer.

The good news is that new therapies are increasing amid financial, clinical, and marketing challenges. However, only 5% of the 7000 known rare diseases have FDA-approved therapies and only about 50% of rare diseases have foundations supporting research. New diseases are diagnosed almost daily.

Approximately 30 million Americans live with rare diseases; 50% are children, of which 30% will die by age five. Desperate to find relief from chronic, painful, multi-system and sometimes fatal ailments, patients seek help from multiple practitioners, many of whom either can’t diagnose or misdiagnose symptoms as common illnesses.

“It’s very frustrating,” says National Organization of Rare Disorders (NORD) Vice-President of Educational Initiatives Mary Dunkle. “These are serious, chronic illnesses with no treatments.” According to Global Genes, a disease is considered “rare” in the U.S. if it affects fewer than 200,000 people; in the U.K., it is fewer than 50,000 citizens per disease.

Fortunately, there is an “explosion of interest” in clinical research of rare diseases, says Michael Murphy, M.D., Chief Medical & Scientific Officer of Worldwide Clinical Trials. “Each one is unique.”

Explosion of Interest

In the first 25 years following passage of the Orphan Drug Act in 1983, only 326 new rare disease drugs were approved. However, in 2015, the FDA approved 21 new orphan drugs, which was 47% of all new drugs approved last year, according to NORD. “This unprecedented activity (rare disease research) is a reflection of an increasingly permissive, innovative science,” says Murphy. “It is out-of-the-box, cutting edge clinical development. Once there is proof of concept, then we need to be creative.”

Within orphan illnesses, doctors often have strong, reciprocal relationships with rare-disease patients and caregivers, managing care co-ordination with diverse specialists, social workers, and payers in a team-oriented care system. Murphy emphasizes that “book” learning does not work in rare-disease application. “Unless you talk to families, nurses, and professionals who manage these difficult conditions, you can’t appreciate the impact of the illness sufficiently to enable the design of a sufficiently sensitive and patient-centric clinical program. You must begin with the patient.” Most rare diseases impact the entire family and involve long-term treatment investments that transcend traditional care management.

Murphy says that, since there are no prototypes, clinical trial designs often are more complicated; there frequently is no established pathway to approval, and clinicians must be cognizant of how a particular condition impacts the daily lives of patients to appropriately structure a program of research.

For example, says Murphy, “you can’t schedule a six-minute walking test [and] fasting for laboratory assessments on the same morning for a child with Duchenne Muscular Dystrophy because the patient may be stiff, weak, and possibly hungry. That will affect the ability to complete a timed assessment, critical in determination of efficacy.”

Designing Rare Trials

Testing for orphan drugs is costly and involves additional pre-trial planning and pragmatism. A clinical test for an illness that affects only hundreds of people will likely need to recruit worldwide. Few centers exist that are capable of engaging in rare disease research, given the unique demands of the illness on staff, patients, and family members and the need for specialized assessments; therefore, clinicians must decide if, and how, patients will travel, possibly thousands of miles and internationally, and how they will be followed up back home when longer term assessments are required.

Researchers who design clinical programs must be pragmatic, says Murphy. “We must think about where we are headed. What is our intent? Who are the stakeholders in the evaluation process who need data? How will these therapies be used in an environment in which novelty alone is not adequate for formulary placement, reimbursement, and appropriate patient access?” Ultimately, he says, “Although the reason for developing new treatments for orphan diseases is humanitarian, that treatment always is embedded in a care system that has appreciable healthcare utilization and financial constraints. It’s about demonstrating value, when novelty alone is not enough.”

If these drugs fail commercially, then all stakeholders may not have been considered in the development process, says Murphy. “First, you need to survey organizations responsible for enabling patient access in a matrix of conflicting healthcare demands and add that to the mosaic of data being examined. Providing that information may involve the use of ‘microenvironments’ for study conduct where every physician-patient transaction could be captured. This could help developers estimate the system impact of a therapy, create a publication strategy to facilitate physician adoption, and enable informed formulary placement and reimbursement decisions.” 

Take, for example, gene therapy, which may be a one-time treatment if “it works as advertised,” says Murphy. (According to Global Genes, 80% of rare diseases are genetic.) “How will insurance companies develop a reimbursement strategy for a one-time treatment application with life-long implications?” Certain orphan drugs, including gene therapies, may only be available at a specific center or in a different country. “Economics becomes more challenging,” says Dunkle. Rare disease populations are smaller. Companies still need to compensate for expenses. “Research and treatments must be sustainable to society. We have to find ways to make the process more efficient.”

Orphan drugs can still reap financial rewards; some have already earned $1 billion annually. Remicade, designated orphan status in 2003 and today used for rare, common, and off-label diseases, earned $9.4 billion in sales in 2014 according to Business Insider. New therapies can treat individuals or patient groups, and off-label usages can earn large profits. In addition, fewer study participants mean shorter, less expensive trials, smaller sponsor investments, and possible tax incentives.

But cost is irrelevant if doctors can’t diagnose, research doesn’t start, and patients can’t access treatments. To combat these obstacles, rare disease experts from NORD are working with 250 member organizations to develop resources to help medical professionals recognize, identify, and treat rare diseases. NORD is also partnering with Medscape and other medical publishers to expand medical professional websites and include diagnostic quizzes, videos, and photos of rare disease symptoms. In addition, NORD is generating a patient caregiver speakers’ bureau in which patients and families speak to medical students and medical professionals. “Families have been eager to help other patients even if it does not help them,” says Dunkle.

NORD also has an advocacy team in Washington, D.C. and an advisory committee overseeing seed grants, including two that led to new drugs. “We are proud that our grants led to this. We need more research,” says Dunkle. “Some diseases have none.”

New Networks

Rare-disease facilities are multiplying. The Undiagnosed Diseases Network (UDN), a clinical research initiative of the NIH, opened the UDN Gateway, an online patient application portal to help diagnose rare-disease patients whose illnesses remain undiagnosed despite clinical investigation. An extension of the NIH Clinical Center in Bethesda, Maryland, the UDN has reviewed more than 3,100 patient applications worldwide since its inception in 2008 and is adding six additional clinical sites across the U.S. (For more information including site locations and the application process see http://undiagnosed.hms.harvard.edu/).

Research and support continue to grow. In 2014, the NIH awarded nearly $29 million to 22 consortia to expand the Rare Diseases Clinical Research Network (RDCRN), led by NIH’s National Center for Advancing Translational Sciences (NCATS). In 2015, the Orphan Product Extensions Now Accelerating Cures & Treatments (OPEN ACT) was proposed, which is bipartisan legislation designed to bring hundreds of therapies to rare disease patients by incentivizing drug makers to “repurpose” FDA-approved drugs for rare diseases and pediatric cancers.

The FDA also helped quicken the pace of rare disease drug development with two draft guidances. The first was a new toxicology requirement for ultra-rare diseases (“Investigational Enzyme Replacement Therapy Products: Nonclinical Assessment”), designed to increase early stage clinical trials in the U.S. The second was the “Duchenne Muscular Dystrophy and Related Dystophinopathies: Developing Drugs for Treatment” guidance, and was the first time an advocacy group’s proposed draft preceded an FDA guidance.

“Patients are dying. Research gives patients hope,” says Dunkle. Next year’s Rare Disease Day is on February 28, a “common” day which will hopefully ring in new common cures for more rare diseases.