JNCI J Natl Cancer Inst (2015) 107(7)
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First Biosimilar Drug Approved for Sale in the United States
By Karyn Hede
New options for biologic cancer treatment are coming for the first time to the
United States, and their arrival could
help drive down costs for some of the
biggest-ticket items in cancer care.
Treatments that interfere with cancer’s biological underpinnings have revolutionized treatment for some cancers.
But their cost now accounts for half
of oncology drug spending—up from
11% a decade ago, according to the IMS
Institute for Healthcare Informatics.
Biosimilar drugs, close copies of patented biologicals, have been available in
Europe for nearly a decade and can cost
up to one-third less than their patented
counterparts. The competitive principle
is similar to that of well-known generics,
but since drugs manufactured in living
organisms tend to be large, complex molecules that can’t be duplicated precisely,
they have been labeled biosimilars.
The U.S. Food and Drug Administration
had been slow to follow Europe’s lead.
But the Biologics Price Competition and
Innovation Act of 2009 began to speed
up adoption of these agents and offer
competition in the health care marketplace. With a framework for adoption in
place, FDA in early March 2015 approved
Sandoz’s filgrastim-sndz, a biosimilar
of Amgen’s filgrastim, which counteracts chronic neutropenia by stimulating
production of immune system–boosting
white blood cells. Although filgrastim is
classified as supportive treatment, other
mainstays of cancer treatment will soon
lose their patent-protected status in
the U.S. The patent on trastuzumab, the
hugely successful targeted monoclonal
antibody therapy for HER2-positive cancers, expired in Europe mid-2014; the
U.S. patent expires at the end of 2018.
Trastuzumab biosimilars from at least
four companies are completing phase
III clinical trials and are expected to be
approved by the European Medicines
Agency within months.
“From an ethical
standpoint—and the
European Medicines
Agency and the FDA
share this—we don’t
want companies to have
to repeat clinical trials,
so we have established a
scientific approach that
both entities have adopted
in order to support global
development.”
Whether biosimilars will help lower
the price of biologics is an open question that may depend, at least initially,
on oncologists’ willingness to prescribe
them. Most oncologists are not aware
of biosimilars. Even if they have heard
of the term, they are confused about
how biosimilars relate to more familiar
brand-name drugs, according to Andrew
Zelenetz, M.D., Ph.D., a medical oncologist at New York’s Memorial Sloan–
Kettering Cancer Center. Zelenetz chaired
the committee that wrote a 2011 white
paper on biosimilars commissioned by
the National Comprehensive Cancer
Network.
A 2011 survey of oncologists attending the annual National Comprehensive
Cancer Network
conference
revealed
that
more than half
of respondents
were either not
at all familiar
(36%) or were
only
slightly
familiar
(19%)
with biosimilars.
But interest is
Leah Christl, Ph.D.
high, with 27%
and 35% responding high and moderate
interest, respectively, in prescribing them.
Not much has changed since then,
according to Zelenetz. He said even his
colleagues at academic medical centers are not clear what biosimilars are.
But he expects that to change shortly,
when pharmacy formularies and payers
start exerting pressure to prescribe these
drugs, which will probably have lower
prices. In Europe and elsewhere, biosimilars are routinely priced 20%–30% less
than the original drug.
Price Pressure
Many questions about the niche biosimilar products will fill remain unanswered. Unlike generic drugs, biosimilar
products are unlikely to be automatically substituted at the pharmacy level,
at least initially. That would require the
product to be deemed interchangeable
with its counterpart, and FDA has yet
to issue firm guidance on interchangeability standards. Unless institutional
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pharmacy and therapeutics committees
can make automatic substitutions, a
delay may occur before people see cost
savings from biosimilars, according to
Zelenetz.
Even the definition of how similar a
copy of a biological drug need be is not
set. That’s the “million-dollar question,”
said Leah Christl, Ph.D., FDA’s associate director for therapeutic biologics.
“A sponsor can’t use a clinical study
to compensate for a lack of analytical
similarity.”
Conversely, if a product doesn’t share a
safety and toxicity profile with the originator drug, it doesn’t meet the biosimilar bar,
and can’t claim to be a biosimilar, she said.
Process Is Product
Biosimilar products start with essentially
the same genetic sequence. But they are
produced in living cells, and the particulars of those production processes
are guarded trade secrets. Because of
the vagaries of biological systems, differences in cell culture systems can
influence the product. That’s why FDA
pays as much attention to the manufacturing process as to the product.
“It is a challenge to run a complex
manufacturing process for biopharmaceuticals,” said Stephen P. Creekmore, M.D.,
Ph.D., chief of the Biological Resources
Branch at the National Cancer Institute.
“There is a risk to using these products,
and the FDA is trying to minimize the risk
to make sure the biosimilar is as close to
the reference product as they can.”
Even if a manufacturer can show
that a product meets the FDA standard for biosimilarity, some oncologists
may be concerned about extrapolation,
Zelenetz said. FDA states that a biosimilar must show analytical comparability
to the U.S. licensed reference product but
might not require full clinical trials for all
indications.
“From an ethical standpoint—and
the European Medicines Agency and
the FDA share this—we don’t want
companies to have to repeat clinical
trials, so we have established a scientific approach that both entities have
adopted in order to support global development,” Christl said.
In practice, that may mean companies
conduct a trial in what FDA calls the most
sensitive population. But the definition
of “most sensitive” may be left up to the
company. For instance, several companies
are in phase III clinical trials to compare
biosimilars of rituximab with its patented
reference product in rheumatoid arthritis
patients. But if these products become
licensed in the U.S., oncologists may not
be comfortable prescribing them for lymphoma, Zelenetz said.
Many oncologists may want to see direct
comparator trials, Creekmore said. “And
I would talk to colleagues about their experience with it, just to be a little cautious.”
Zelenetz is on the biosafety monitoring
board for a company developing a biosimilar,
but he has no financial stake or stock in any
company and is conducting no clinical trials
on any of these products.
© Oxford University Press 2015.
DOI:10.1093/jnci/djv191
First published online July 3, 2015
Policymakers Work To Develop E-Cigarette Guidelines and
Restrictions
By Mike Fillon
Are e-cigarettes different enough that
they can’t be regulated like cigarettes?
Are they less harmful than their tobacco
counterparts? Are e-cigarettes a public
nuisance? Do restrictions or bans compromise individual freedoms? Should
e-cigarettes be taxed like cigarettes?
The emergence of nicotine-laced
e-cigarettes has caught everyone, including government regulators and policymakers, by surprise. National guidelines
or regulations legislation has lagged,
and the number of e-cigarette users has
soared.
At the federal level, the answers are
nowhere near settled. “Meaningful action
by the Food and Drug Administration
is years away, if ever,” said Stanton
A. Glantz, Ph.D. Glantz is professor of
medicine in the division of cardiology,
the American Legacy Foundation distinguished professor of tobacco control, and
director of the Center for Tobacco Control
Research and Education at the University
of California, San Francisco, school of
medicine.
As federal regulators struggle to formulate an overarching national policy,
state and local governments are devising
their own strategies. Some locales have
sought to prevent the sale of e-cigarettes
to minors, whereas others have taken
drastic steps to either tax or limit where
e-cigarettes can be used:
• New Jersey treats e-cigarettes the
same as tobacco cigarettes, and the
same restrictions apply to both under
the New Jersey Smoke-Free Air Act.
• In July 2010, New Hampshire made
selling e-cigarette to minors illegal.
• In April 2014, New York City banned
use of e-cigarettes in any place where
smoking regular cigarettes is pro-
hibited, including bars, restaurants,
offices, parks, and beaches.
• Maryland banned sales to minors.
Taking it even further, the California
Department of Public Health (CDPH)
released the State Health Officer’s Report
on E-cigarettes: A Community Health Threat
(http://www.cdph.ca.gov/Pages/NR1512.aspx). “This report was released to
inform health care providers and the
public about the health risks associated
with e-cigarettes,” said CDPH spokesman
Scott Sandow. “The report concludes that
e-cigarettes should be strictly regulated
and that restrictions on marketing to
youth, access by youth, and poison prevention are critical areas where regulation is needed to protect children and
teens from harm caused by e-cigarettes.”
E-cigarettes are being marketed
as healthier alternatives to cigarettes,