FDA's biosimilars pathway officially has been open
since enactment of the Patient Protection and Affordable Care Act in March
2010, but biosimilars companies are just starting to get a good idea of what
the agency will require.
Senior FDA officials have told
BioCentury the agency will create a two-step process. Companies first will
submit analytic data showing how similar their compounds are to an FDA-approved
innovator version. The agency then will determine on a case-by-case basis how
much animal and clinical data are required for approval.
This is fundamentally different
from EMA, which has published or announced it is writing guidelines that
chart the requirements for developing six classes of biosimilar products (see
"The Other Side of the Pond").
Rather than lay out such
specific requirements, FDA is creating a pathway that will allow companies with
strong analytical capabilities to get biosimilars to market more rapidly, and
less expensively, than companies that lean more heavily on clinical
It is also becoming clear that
both EMA and FDA could impose substantial costs by requiring a biosimilar be
compared to an innovator that is approved in the jurisdiction where the
biosimilar would be marketed.
This could slow the
introduction of biosimilars in the U.S. by companies that were looking for
quick, relatively inexpensive development programs based on European clinical
and marketing experience (see "Foreign Labels").
It also could hamper the
development of globally branded biosimilars.
Step 1: Similarity
A number of prospective
biosimilars manufacturers, including companies that manufacture innovator
products as well as companies that market biosimilars in Europe, have had
preliminary discussions with FDA, the agency's Rachel Behrman said last week on
BioCentury This Week, BioCentury's public affairs television program.
Behrman, who is associate
director for medical policy in the Center for Drug Evaluation and Research,
said the agency will spell out in a series of guidance documents how it will
implement a two-step approach to reviewing biosimilars.
At least one guidance will be
released before year end, she said in FDA's first media interview on the
Rather than create a standard
set of preclinical and clinical data required to demonstrate biosimilarity to a
reference product, Berman said the agency first wants to see how strong a case
the applicant has made that its product is analytically similar to the
innovator and then decide what other data will be required.
"First we have to
understand from the analytics everything we possibly can about the molecule,"
she said. "Once we review and fully understand that information, then we
will be able to provide advice on the extent of animal and human testing."
Behrman cited FDA's approval of an application from Momenta
Pharmaceuticals Inc. for a generic version of enoxaparin, a low
molecular weight heparin marketed by Sanofi
as Lovenox, as an example of the different perspectives FDA and EMA have on the
power of analytical characterization.
Enoxaparin, a complex
carbohydrate, is regulated as a drug in the U.S., not a biologic. Nonetheless,
Behrman cited it as an example of how "we may be able to take the European
experience [with biosimilars] and go one step further."
While an EMA biosimilars
guideline mandates clinical trials for low molecular weight heparin products,
FDA approved Momenta's M-Enoxaparin based solely on analytical data (see
BioCentury, Aug. 2, 2010).
Regulatory decisions about
bio-similars, Behrman said, are driven by an entirely different paradigm than
is used to review the safety and efficacy of innovator products. "We
already know that the molecule is safe and effective. We are trying to
establish that this biosimilar will have the same effect in a patient, without
any clinically meaningful differences," she told BioCentury This Week.
Several companies that plan to market biosimilars in the U.S.,
including Momenta and Novartis
AG's Sandoz division, have embraced the idea that the degree of
analytical similarity should determine the amount of animal and clinical data
required to demonstrate biosimilarity. Innovators, however, have not
universally embraced the concept (see "Is Comparable Similar?").
Inc., which has recently announced its own biosimilars strategy, is not
convinced that any amount of analytic data is sufficient to justify an abbreviated
clinical package (see "If You Can't Beat 'Em . . ." A5).
"We are not comfortable
with the idea that if you can get an analytical package to look as close as
possible [to the reference product] you have sufficiently addressed all the
relevant safety issues and must only do limited studies," Gino Grampp,
regulatory affairs director at Amgen, told BioCentury. "We think it is
important to evaluate safety and immunogenicity over a longer period of time."
Analytic, and possibly
clinical, data also will be key to FDA's decisions about whether it will allow
a biosimilar to extrapolate from studies demonstrating safety and efficacy for
one indication to all of the indications on the innovator's label.
FDA will make decisions on
extrapolation on a case-by-case basis, Behrman told BioCentury This Week.
These decisions "will depend on the biologic plausibility; it will depend
on the population; it will depend on really how close they are," she said.
Extrapolation is an economic
incentive for using the biosimilars pathway, rather than attempting to obtain a
standard BLA, according to Mark McCamish, head of global biopharmaceutical
development for Sandoz.
The U.S. biosimilars pathway "has
huge opportunities because of the possibility to extrapolate to multiple
indications, and the unique ability in the U.S. to get interchangeability,"
he told BioCentury. "On the down side, there are critical limitations,
including the IP process one has to go through."
The patent litigation section
in the U.S. biosimilars law "erects a significant barrier" to using
the pathway because it forces biosimilars companies to disclose details on
their proprietary manufacturing processes to the manufacturers of reference
innovator products, John Engel, a partner at the law firm Engel & Novitt LLP,
said on BioCentury This Week.
According to Engel, biosimilars
companies will have to decide - "do you want to put yourself in the
position where you are turning over your trade secrets to your fiercest
competitors? That has been the biggest disincentive as we've been evaluating
how companies should proceed with their applications."
Sandoz hasn't disclosed which
approach it is taking for specific products. But according to McCamish, the
factors will include whether a product "has so many indications that it
makes no sense to file a BLA for each. Or does it have a predominant
indication," so extrapolation isn't as important.
Even more than extrapolation of
indications, the potential to have a product classified as interchangeable with
the innovator - and hence potentially automatically substitutable - is the
biggest potential upside to using the FDA pathway, according to McCamish.
interchangeability works like generic drug interchangeability, it would allow
biosimilars to rapidly capture most of the innovator's market share with
According to Behrman, FDA views
approval of a biosimilar and classifying it as interchangeable as sequential
steps. To accomplish the second step, she said, sponsors will have to surmount
high hurdles, including demonstrating the safety of switching back and forth
between a biosimilar and an innovator.
"I would have to be
comfortable as a physician, we would have to be comfortable as regulators, that
a person could go back and forth and back and forth without any compromise in
the safety or efficacy of the product to declare it interchangeable,"
Behrman said. "That is doable, but that is sequentially a step after
biosimilarity has been established."
Whether it is part of initial
approvals or requires a separate submission after a product has been on the
market, several companies that hope to get into the U.S. biosimilars
marketplace say they expect to obtain interchangeability.
For example, Momenta's
corporate strategy is based on the belief that "we can go after
substitutable biologics and that analytics are really going to be the core
towards what's going to drive to that strategy," Craig Wheeler, Momenta's
president and CEO, said at the Deutsche Bank healthcare conference last week.
In contrast, James Daly, SVP of
North American commercial operations at Amgen, told the conference that he "wouldn't
anticipate interchangeability with biosimilars."
Referring to Behrman's comments
on BioCentury This Week, Daly added: "There was some concern in the
last few days on the Lovenox implications as an analog. There's a world of
difference between Lovenox and large complex proteins. There really is - in
terms of analytics, in terms of the ability to show comparability."
Daly concluded that the generic
enoxaparin approval was based on a "sameness criteria that is literally
impossible for biologics, for large molecules."
Speaking on BioCentury This
Week, Behrman noted there has been some "inadvertent switching"
among biosimilar and innovator biologics in Europe.
Amgen's Grampp said it is
important to "differentiate between switchability and interchangeability"
"There are five or six or
seven ESAs in Europe. Many have shown you can switch from one product to
another under the supervision of a physician," he said. "Our concern
with interchangeability is that it could be occurring multiple times and
essentially blinded to the physician or patient."
While the scientific standards
FDA will use to review biosimilars applications are slowly coming into focus,
companies investing in biosimilars for the U.S. market have to factor in a
possible wildcard: several lawsuits pending in federal courts that challenge
the constitutionality of the Patient Protection and Affordable Care Act.
If the U.S. Supreme Court
ultimately rules that provisions of the act are unconstitutional, it would also
have to determine if those portions can be separated from the overall law,
Daniel Kracov, a partner at the law firm Arnold & Porter LLP, said on BioCentury
This Week. If not, the entire law, including its biosimilars provisions,
could be scrapped.
Momenta noted this possibility
in a March 10 SEC filing, reporting that if the "legislation is declared
unconstitutional, is significantly amended or is repealed, our opportunity to
develop biosimilar (including interchangeable) biologics could be lost and our
business could be materially and adversely affected."
Inc. (NASDAQ:AMGN), Thousand Oaks, Calif.
Idec Inc. (NASDAQ:BIIB), Weston, Mass.
S.A., Warsaw, Poland
Lilly and Co. (NYSE:LLY), Indianapolis, Ind.
Medicines Agency (EMA), London, U.K.
Inc., South San Francisco, Calif.
Canada, Ottawa, Canada
& Johnson (NYSE:JNJ), New Brunswick, N.J.
Pharmaceuticals Inc. (NASDAQ:
MNTA), Cambridge, Mass.
AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland
Inc. (NYSE:PFE), New York, N.Y.
(SIX:ROG; OTCQX:RHHBY), Basel, Switzerland
(Euronext:SAN; NYSE:SNY), Paris, France
Pharmaceutical Industries Ltd., (NASDAQ:TEVA), Petah Tikva, Israel
Food and Drug Administration (FDA), Silver Spring, Md.