f ever a drug development effort called out
for priority review and approval, this was
it. A U.S. pharmaceutical company was
developing a treatment for hypophospha-tasia, a progressive, ultra-rare metabolic
disease for which only supportive therapy was available.
Asfotase alfa, an innovative enzyme replacement drug,
was the first real hope for those diagnosed with HPP, a
disease that attacks bones and multiple systems of the
body with devastating consequences.
The Food and Drug Administration granted the compound Breakthrough Therapy designation and issued
the developer a Rare Pediatric Disease Priority Review
Voucher, which confers priority review to a subsequent
drug application that would not otherwise qualify for
priority status. The voucher program encourages development of new drugs and biologics to prevent or treat
rare pediatric diseases. Meanwhile, the European Medicines Agency conferred orphan status and provided
scientific advice through its Committee for Medicinal
Products for Human Use.
The expedited development and subsequent approval
of the drug – on the market now in the United States, European Union, Japan, and Canada – reflects a large and
promising trend in the battle against rare diseases. Concerted effort by governments, regulators, and industry is
expanding development of new therapies, opening doors
and giving fresh hope to the hundreds of millions who
suffer from the more than 7,000 known rare diseases.
To understand the rising urgency in developing and
approving treatments for these conditions, it’s helpful
to recognize that “rare disease” is largely a misnomer.
While no single condition claims many victims, there are
a lot of them. An estimated 30 million Americans (that’s
almost one in 10) live with a rare condition, according to
rare disease advocacy group Global Genes. The number
is about the same in Europe, and worldwide, it’s around
350 million. Even more tragic, half of the known rare
diseases afflict children.
Considering the time and expense involved in developing new treatments, it’s hardly surprising that there
are only about 400 approved therapies, and that 95 percent of diseases today go untreated. While 2015 was a
landmark year for these so-called “orphan” drugs, with
21 approved in the U.S. and 18 in the European Union,
the industry is still just scratching the surface.
Since the U.S. Orphan Drug Act passed more than 30
years ago, U.S. regulators have provided extensive guid-
ance and resources to support rare disease research. Or-
phan designation qualifies drug companies for develop-
ment incentives that include:
• Financial grants
• Increased access to regulatory agencies for
scientific support and interaction
• Protocol assistance
• Extended periods of market exclusivity
• Fee reductions and waivers
The FDA and EMA are showing unprecedented sup-
port in addressing this vast unmet need, aiming these
efforts largely at the biotech and specialty pharma com-
panies that are at the forefront of orphan drug develop-
ment. Because many of these companies are very small
– some pursuing a single compound – they often lack
the resources to research and make best use of what’s
available. Premier Research frequently counsels these
companies, and here’s some of what we’re telling them.
Last fall, the FDA awarded 18 research grants for prod-
uct development in rare diseases. Averaging just over
$1 million each, they include $1.1 million to contin-
ue developing a drug that makes tumor cells in HPV
patients more susceptible to immunologic attack and
$1.6 million for a vascular-targeted prodrug to treat
recurrent glioblastoma. Other FDA initiatives include
the Orphan Products Natural History Grants Program,
which in fiscal 2017 will fund $2 million in rare dis-
ease-related natural history studies.
The EMA, meanwhile, is two years into Horizon
2020, the largest research and innovation program in
its history and one of the biggest worldwide. The program has budgeted nearly 80 billion euros through
2020 to promote scientific excellence and strengthen
Early regulatory engagement
Let’s face it: This is a business of longshots. More than
90 percent of the drugs that reach clinical testing fail,
and when you further consider the treatments that don’t
make it that far, it’s clear how much is at stake. Recognizing this reality, U.S. and European regulators increasingly push for earlier involvement with sponsors, who –
to their credit – are mostly embracing the opportunity.
At a recent industry conference in Europe, a speaker
from EMA was vocal in calling on sponsors to engage
early to ensure efficient and scientifically rigorous processes. The agency’s Innovation Task Force, offering
an information platform for early dialogue on scientific, technical, and regulatory issues, is one of multiple
avenues for early involvement. The FDA is always willing to talk with sponsors. Sponsors can request formal
Type B (pre-IND, end of phase 2) meetings or Type C
(general guidance) meetings throughout product development.
More sponsors also are turning to a process called
precompetitive collaboration, working with government
organizations, academic research centers, and even competitors. The extreme complexity and paucity of data inherent in rare drug research make these efforts time-consuming and expensive and produce a terrible success rate.
Precompetitive collaboration played a major role in HIV/
AIDS research as competing pharma and biotech companies joined with academic researchers and government
research institutes to answer a challenge that demanded
the best of their collective ingenuity.
Some level of precompetitive discourse is almost a necessity today, prompting the 2014 launch of the Accelerating Medicines Partnership. AMP is a public-private
partnership among the NIH, FDA, 10 biopharmaceutical companies, and multiple nonprofit organizations
intended to transform the current model for developing
new diagnostics and treatments by identifying and validating promising biological targets for therapeutics.
Collaboration between U.S. and EU regulators is also
on the rise. The FDA and EMA have greatly increased
their level of cooperation and information-sharing in
recent years. There are frequent interactions, and they
maintain structured scientific and regulatory working
groups, or “clusters.” In 2015 they established a cluster
on patient engagement to share experience and best
practices around patient involvement in drug develop-
ment, evaluation, and post-authorization activities. The
Pediatric Cluster between FDA and EMA has been in
place since August 2007, providing a forum to discuss
product-specific pediatric development and topics relat-
ed to product classes with the objective to enhance the
science of pediatric trials and to avoid exposing children
to unnecessary trials. The regulatory agencies from Ja-
pan (Pharmaceutical Medicines and Device Agency,
PMDA), Canada (Health Canada), and Australia (Ther-
apeutic Goods Administration, TGA) are also partici-
pants joining in 2009, 2010, and 2014.
Better access to government data
Another boon to researchers is rapidly expanding
access to the results of scientific research funded by
government agencies, information that resides in hundreds of data-sharing repositories. The U.S. Department of Health and Human Services in 2015 issued
a public access policy covering its largest operating
divisions: the FDA, the NIH, the Centers for Disease
Control and Prevention, and the Agency for Healthcare
Quality and Research.
The agency has two goals: to make publications resulting from the research it funds freely available to the
public, and to make the information available in digital
formats (the effort is young, so the digital infrastructure is still emerging). HHS Secretary Sylvia Burwell
declared this “an inflection point in history” in describing plans to give the public maximum value from federally funded health research data.
Recognizing the urgency
Any discussion of government support for orphan drug
development needs to acknowledge legislative action to
promote new treatments. The 21st Century Cures Act,
an effort to accelerate approval of medicines for conditions currently lacking cures, was signed into law in
December 2016. Specific incentives for rare disease development include reauthorization of the Pediatric Rare
Disease Priority Review Voucher program, designed to
encourage development of treatments for rare pediatric
diseases, through September 30, 2020. In addition, provisions were included to allow for prospectively planned
and designed natural history observational studies to be
eligible for governmental assistance and for reliance on
data from previous studies conducted by the same sponsor (or another sponsor with right of reference to that
data) in previously approved applications for products
that address an unmet medical need.
Legislation can prompt regulatory change, but doesn’t
necessarily need to precede it. It’s clear that the U.S. and
European governments recognize the urgency in promoting development of orphan drugs and are committed to
giving the subject continued high priority. medadnews
Dr. Lisa Pitt is VP, Global Regulatory Affairs, Premier Research.
Angi Robinson is Executive Director, Pediatrics & Rare Disease,
orphan drugs extrafeature