Orphan Diseases
one. Now, Dr. Regier is hoping to nurture
young investigators’ interests in rare diseases.
She is education director of the Rare Disease
Clinical Research Network’s Rare Disease
Training Program, which launched in 2015
with the goal of teaching the “characteristics
that we see in people who succeed and stay in
rare disease research.” 8
Over eight weeks, program workshops
introduce researchers to strategies for con-
ducting statistical analyses in studies with few
patients, fostering trust in patients and fami-
lies, building patient networks, and obtaining
funding. “We started with 20 people, and last
year, we had almost 40 applications,” said Dr.
Regier. “Now, we’re accepting 30 people a year
into the program.”
While more and more trainees are learning
about rare diseases, Dr. Zakai explained that
reaching young trainees is only part of the
battle. Once physicians are out of training,
their time becomes billable, and it can be dif-
ficult to keep them involved in research of any
kind, let alone rare disease research.
“From a recruiting perspective, hospitals
and universities are very risk-averse, so it’s
hard to get them to take a risk on a person
to provide the protected time for research
nowadays,” he said. “Ten or 15 years ago, it
was much easier to justify a decision with
protected time to allow physician–scientists to
build a research career. Now, it’s much more
difficult to get these spots approved without
funding already in hand, meaning that young
investigators already have a grant that protects
their time.”
Federal Support
The FDA has stepped in to address some of
these challenges. One approach has been to
co-host workshops like the FDA-ASH SCD
Clinical Endpoints Workshop in October
2018, with a goal of identifying opportunities
to bring uniformity and standards to existing
SCD endpoints, identify gaps, and propose
development of new endpoints for future
research. 9 Similarly, the Product Development
in Hemophilia workshop, held in December
2018, brought together staff from the FDA’s
Oncology Center of Excellence, the Center for
Biologics Evaluation and Research, and the
Center for Drug Evaluation and Research to
discuss the development of patient-experience
and patient-reported outcomes for use in tri-
als of novel hemophilia products. 10
But, undoubtedly, the agency’s largest
impact on rare disease treatments began in
the 1980s with the Orphan Drug Act. 11 This
legislation was designed to incentivize phar-
maceutical companies to take the financial
risk of developing drugs to treat rare diseases.
The act offered three main incentives: federal
grants for orphan drug research, a 50-percent
tax credit to help cover the cost of clinical
trials, and seven years of marketing exclusivity
for products approved as orphans.
By some measures, the act has been
extraordinarily successful. From 1967 to 1983
(the 16 years immediately before the act was
passed), only 34 drugs were approved for rare
diseases; since the act was passed, the FDA
44
ASH Clinical News
has approved more than 500 orphan drugs. 3
Dr. Cairo, whose research has been sup-
ported by an Orphan Products Clinical Trials
Grant, said the act has had an “extremely
positive” influence on his work. “I can’t say
enough about how much and how critical the
FDA has been in creating this grant mecha-
nism for orphan diseases,” he stated. “We
would not be able to accomplish what we’ve
done or cure all the patients we’ve cured with-
out that support.”
Orphan Drug Act Controversies
The incentives, though, may have worked a
little too well: So many companies applied for
orphan drug designation for their products that
the FDA couldn’t keep up, creating a backlog
of 138 overdue drug applications by 2017.
According to the FDA, reviewers caught up and
erased the backlog in September of 2017. 12
In the 16 years
prior to the Orphan
Drug Act’s passage,
only 34 drugs were
approved for rare
diseases; since it
was passed, the
FDA has approved
more than 500
orphan drugs.
The legislation also included a well-known
loophole that allowed companies to skip con-
ducting crucial pediatric trials for products
designated as orphan drugs. Manufacturers
have exploited this exemption, seeking to des-
ignate their products as orphan drugs to avoid
the pediatric study requirement. In 2018, the
FDA effectively closed this loophole, issuing
a draft guidance for industry that clarifies
orphan drug requirements for pediatric sub-
populations of a common disease. 13 (Editor’s
note: The FDA’s Office of Orphan Products
Development [OOPD] was unavailable to com-
ment for this article because of the government
shutdown.)
Others believe that the seven-year period
has given opportunistic companies the ability
to charge exorbitant prices for orphan prod-
ucts. When the seven-year exclusivity for one
orphan designation runs out, some companies
seek orphan status for the same drug for a dif-
ferent indication, gaining another seven years
of market exclusivity.
A 2017 Kaiser Health News investigation
found that 70 of 450 orphan drug approvals
weren’t new; they were already being mar-
keted for common diseases. 14 For example,
in hematology, pegfilgrastim (Neulasta)
was initially approved for mass-market use,
but subsequently was approved for orphan
indications.
A November 2018 investigation from the
Government Accountability Office (GAO)
also points to some areas for improvement
in the orphan drug program, reporting that
many applications were not thoroughly evalu-
ated. 15 “GAO’s analysis of 148 designation
review templates found that FDA does not
consistently record or evaluate background
information when making designation deci-
sions,” the authors wrote.
In many cases, applications that were miss-
ing important background information were
approved, and reviewers did not always verify
the information they did have. “Specifically,
we found that OOPD granted designation to
11 applications where the reviewer did not
record prior orphan designation history, to 13
applications where the reviewer did not docu-
ment independent verification of the manu-
facturer’s population estimate, and to two
applications where the reviewer did neither,”
according to the report.
Critics also have pointed to other over-
sights in the Orphan Drug Act that could
be exploited. For example, pharmaceutical
companies can split diseases into smaller
populations, suggesting a drug only be used
for patients in particular stages of disease, or
repeatedly apply for more orphan designa-
tions for the same drug. Some of the most
widely used drugs also have orphan drug
designations, like Humira (adalimumab), the
best-selling drug in the world. It initially was
approved to treat rheumatoid arthritis but
later received orphan designations to treat
juvenile rheumatoid arthritis, Crohn disease,
and uveitis. 16
Prices Reaching Rare Heights
Orphan diseases are getting more attention
recently, and so are the prices for their treat-
ment. Despite the financial incentives offered
by the Orphan Drug Act, companies continue
to price drugs for rare disease in the hundreds
of thousands of dollars per patient per year.
As part of the Kaiser Health News investiga-
tion, EvaluatePharma found that out of the
10 drugs with the highest annual sales (in
total dollars), seven were considered orphan
drugs. 14 By 2020, it is predicted that orphan
drugs will account for 20 percent of all drug
sales (excluding generics).
The rationale behind pricing is that orphan
drugs take longer to bring to market, accru-
ing more in research-and-development costs.
However, a December 2016 report prepared
for Congress suggested that the average cost
to develop an orphan drug was less than half
that of a drug for more common diseases – $1
billion compared with $2.6 billion. 16
A 2017 study commissioned by NORD
appears to allay concerns about the pricing
of orphan drugs, however: Only 7.9 percent
($36 billion) of drug spending in the U.S.
went toward orphan designations of orphan
drugs, while another $100 billion was spent
on nonorphan uses of drugs with orphan
February 2019