FEATURE
myriad research and treatment challenges, explained
David Fajgenbaum, MD, MSc, assistant profes-
sor of medicine at the University of Pennsylvania’s
Perelman School of Medicine. Dr. Fajgenbaum
also is executive director of the Castleman Disease
Collaborative Network (CDCN), which brings
together scientists, patient groups, academic institu-
tions, and other organizations to improve the diag-
nosis and treatment of Castleman disease – a rare
lymph node disorder he was diagnosed with during
his third year of medical school.
Foremost among the challenges Dr. Fajgenbaum
outlined is the difficulty of running studies with
so few patients available to participate in trials.
“Of course, the fewer patients, the fewer data are
going to exist,” he said. And the patients who can
supply data are likely to be spread out geographi-
cally, making collecting samples and running tests
exceptionally expensive and time-consuming.
Rare diseases also have complex presentations:
Approximately 80 percent of rare diseases are
genetic and continue throughout a patient’s life.
And, while some patients don’t display symptoms
until adulthood, about 50 percent of rare diseases
affect children. Symptoms can vary from patient to
patient and can change as patients age.
The limited information about the natural pro-
gression of rare diseases, combined with a variation
in symptoms and severity, mean that designing
ideal endpoints for clinical trials for these condi-
tions is challenging. According to a report from the
Tufts Center for the Study of Drug Development,
the average time from first patent filing to market-
ing approval of an orphan drug is 15.1 years – 2.3
years longer (an 18% increase) than for therapies
for more common diseases. 4
Still, Dr. Fajgenbaum is optimistic about the
future of rare disease drug development. “So much
work has already been done for the more common
diseases, so there is just more low-hanging fruit
and more opportunity for major strides in the rare
disease space,” he said. Discoveries in rare diseases
can dramatically change patients’ lives, he sug-
gested, while discoveries in more common diseases
are likely only to lead to incremental improvements
in known treatment strategies.
The Rarity of Rare Disease Specialists
Even as rare diseases gain more attention,
physicians like Courtney Fitzhugh, MD, a
Lasker Clinical Research Scholar at the National
Institutes of Health’s (NIH’s) National Heart,
Lung, and Blood Institute, said there remains
a shortage of providers who specialize in rare
diseases. This is true even for more common
rare diseases like sickle cell disease (SCD), Dr.
Fitzhugh’s specialty.
“There are not many adult providers taking
care of patients with sickle cell,” she said, explain-
ing that the scarcity of clinicians trained in the
management of SCD means pediatric hematolo-
gists are stretched thin. “It’s hard to find doctors for
older pediatric patients who need to transition to
adult care.”
It also is common for institutions to struggle
to find clinical trial participants, according to
Mitchell Cairo, MD, chief of pediatric hematol-
ogy, oncology, and stem cell transplantation at New
York Medical College.
“Participating in clinical research trials can
be cumbersome for a patient and a family. Many
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patients with rare diseases like SCD come from
socioeconomic backgrounds that provide over-
whelming barriers that can prohibit them from
actively being involved, whether it’s family support,
transportation, insurance coverage, et cetera.”
These impediments have contributed to low
rates of clinical trial participation, Dr. Cairo added.
“I would like to find ways to solve that issue over
time, by providing additional funding over and
above the regular funding to help families be able
to participate.”
“Rare disease
foundations are
playing a greater
role in raising
awareness about
diseases, pushing
forward guidelines,
and bringing
together consortia
... to make more
progress . ”
—DAVID FAJGENBAUM, MD, MSc
On the pharmaceutical development side, inad-
equate funding is frequently blamed for the lack of
treatments for rare diseases: With so few patients
to use an approved orphan drug, the return on
investment for years of research doesn’t make fis-
cal sense for most pharmaceutical companies. To
address this concern, the FDA’s definition of an
orphan drug includes a stipulation that companies
can apply for an orphan drug indication if their
product is intended for use in diseases that affect
more than 200,000 people but are not expected to
recover the costs of developing and marketing the
drug. 3
The Missing Link: Advocacy Groups
The greater focus on rare diseases appears to have
coincided with a greater understanding of the
human genome and the genetic basis of diseases,
according to Dr. Cairo, which “is pointing us in a
direction of therapeutic opportunities that really
didn’t exist before in these rare diseases.”
Alongside this breakthrough in knowledge,
patient advocacy groups – which are primarily
known for raising awareness and funds for re-
search – have started stepping up to act as liaisons
between researchers and institutes and between
patients and pharmaceutical companies. The Cystic
Fibrosis Foundation’s partnership with Vertex
Pharmaceuticals is a widely cited example of col-
laboration between advocacy organizations and a
pharmaceutical company; the agreement, in which
the foundation invests in the for-profit company, has
helped produce the first three disease-modifying
drug approvals for cystic fibrosis. 5
“Rare disease foundations are playing a greater
role in raising awareness about diseases, pushing
forward guidelines, and bringing together consor-
tia,” Dr. Fajgenbaum said. “These types of proactive
efforts from rare disease foundations are getting
the attention of physicians and researchers and cer-
tainly providing resources to make more progress.”
Dr. Fajgenbaum established the CDCN in
2012 with a goal of accelerating treatments for
Castleman disease in four main areas: a research
plan, strategic collaborations that span the globe,
awareness and fundraising, and patient engage-
ment. The network fills a hole and acts as a “cen-
tral player between all of the various aspects of
the health-care industry,” he noted. In addition to
creating a network of researchers and patients, the
group has identified key goals for future research
and established diagnostic criteria for HHV-8–
negative multicentric Castleman disease. 6
The American Society of Hematology also
has taken a proactive stance in supporting rare
diseases research: In September 2018, the Society
announced the launch of an SCD clinical trials
network, under the auspices of the newly formed
ASH Research Collaborative (ASH RC), “to ac-
celerate the development of new therapies for a
patient community that has very few treatments
and curative options.” 7 The network will connect
trial locations and sponsors, provide consulting
services to each site, and encourage patient input
and involvement. Other efforts will focus on reduc-
ing inefficiencies and redundancies in the research
landscape, like establishing a single institutional
review board to serve all research sites and trial
sponsors, along with a central data repository – the
ASH RC Data Hub – to aggregate and facilitate
sharing of clinical data. The group plans to initiate
its first study in the fall of 2019.
“Enrollment and completion of clinical trials
in SCD have historically been slow and costly,”
said 2018 ASH President Alexis Thompson, MD,
MPH, of the Ann & Robert H. Lurie Children’s
Hospital of Chicago. “Establishing an organized
network that will accelerate the completion of
clinical research studies and bring new therapeutic
options to patients more quickly is one of the most
meaningful ways ASH can make a difference in
the lives of people with this debilitating, chronic
disease.”
Physician Recruitment
Like Dr. Fajgenbaum, many rare disease specialists
are drawn to their area of expertise by personal
experience. “My connection obviously is personal,
and I would say that’s the case for most physicians
who get involved in rare disease,” he said. “They
treat a patient who has a rare disease, they recog-
nize the challenges or how much work still needs
to be done, and they start to look into it a little bit
more.”
For example, Dr. Fitzhugh was introduced to
SCD at an early age, when her mother’s organiza-
tion hosted a Christmas party for children living
with SCD.
Debra Regier, MD, PhD, a geneticist at
Children’s National Health System in Washington,
DC, learned about the challenges of treating rare
diseases when her nephews were diagnosed with
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