Hospira, Inc. started Phase III clinical trials for generic
erythropoietin (EPO) in late 2011. When the Lake Forest, Ill. company submits
an application to the Food and Drug Administration (FDA) for its biosimilar
EPO--and that won't be until at least 2015--it could be the first U.S. company
to take advantage of the new expedited
approval pathway for biosimilars established by the Biologics Price
Competition and Innovation Act of 2009 (BPCIA), which was an amendment to the
health care reform bill called the Affordable Care Act. Hospira's generic EPO
would be an alternative to Amgen's Epogen®.
But with the FDA
set to issue final guidance on requirements for what are called 351(k) expedited
biosimilar applications and inaugurate a new biosimilars user fee program to
help pay for examination of those applications, there will be a number of
entrants in the race to be the first biopharma company into the 351(k)
pipeline. Momenta Pharmaceuticals signed a collaborative agreement last
December with Baxter Healthcare with the intention of developing biosimilar and
potentially interchangeable biologic products. James Roach, M.D., Chief Medical
Officer, Momenta, says the draft FDA guidelines published in February allow for
the possibility the FDA could approve a biosimilar without the company
necessarily having to go through time-consuming, costly clinical trials, as
Hospira is doing. Those draft guidelines will be finalized, possibly with
alterations, probably by summer 2012. "However, we understand the burden
will be on the sponsor to provide a data package that scientifically
justifies a reduction in requirements
for preclinical or clinical studies," Roach adds. "And we think that
bar should be high for achieving biosimilarity at one level and
interchangeability at another level."
"Interchangeability" is a higher
designation than "biosimilarity" and would allow a pharmacist to
substitute a biosimilar for the brand-name reference drug prescribed by the
physician without the physician's prior approval. Health insurers and employers
particularly are anxious for the FDA to set the interchangeability bar as low
as possible, so that their prescription drug costs are reduced to the maximum
extent possible.
Roach hopes to obtain reduced FDA testing
requirements for biosimilars, including interchangeable products. He believes
the approach the company took to develop a generic version of enoxaparin (Lovenox), a low molecular weight
heparin the company developed with Sandoz, conceptually applies to biosimilars.
While Lovenox is not technically a biosimilar, it is a complex drug derived
from pig intestines. Biosimilars are derived from cell cultures and other
living organisms. "We did a small, normal volunteer study for enoxaparin
but in accordance with generic drug requirements were not required to perform
clinical trials to independently establish safety and efficacy," Roach
states.
Avoiding a full complement of clinical
studies might lead not only to earlier product entry, but also to lower cost
entry for the developer. Hospira's U.S. clinical trials for biosmilar EPO will
cost in the neighborhood of $100 million - $200 million, according to Sumant Ramachandra, Senior
Vice President, Research & Development and Medical Affairs, and Chief
Scientific Officer, Hospira.
Once it opens the door to 351(k)
applications, the FDA will have to walk a fine line between imposing onerous
testing requirements and speeding approval of biosimilars which will save
consumers and payors, federal and private, billions of dollars a year. Roach estimates that generic
enoxaparin--again, technically not a biosimilar--has saved health insurers,
employers and consumers somewhere between $750 million to $1 billion since it
was introduced. The Pharmaceutical Care Management Association commissioned a 2007 report
that projected Medicare Part B savings from biosimilars at $3 billion by
FY2016.
Those savings are already being
felt in Europe where the European Medicines Agency has approved a number of
big-molecule biosimilars such as
Hospira's Retacrit™ and
Nivestim™, a biosimilar version of filgrastim. Sandoz is selling two
biosimilars in Europe, its anemia medicine Binocrit® (epoetin alfa) and
oncology medicine Zarzio® (filgrastim). They are generally priced 15-30 percent
below the reference drug. But "take up" has been slow because of the
lack of interchangeability designations. However, U.S. companies generally have been hesitant to jump into the FDA biosimilar pipeline without some formal clarification of what the FDA will expect to see data-wise in applications. In order to avail themselves of this new section 351 (k) of the Public Health Service Act, companies have to show that their biosimilar "is highly similar to the reference product notwithstanding minor differences in clinically inactive components'' and that "there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product.''
Companies such as Hospira and Momenta have generally
applauded the FDA draft 351(k) guidelines issued in February. "The
guidance is pretty solid, although we have caveats," states Hospira's Ramachandra. "When you read draft guidance it
is very broad. It gives the FDA to adjudicate. We believe in that approach. It
is hard to legislate or regulate this type of field when tools still being
built it."
The most controversial and important
issue surrounding the draft (and final) guidance is the FDA's "take"
on interchangeability. The FDA says in the draft that companies can apply for
an interchangeability designation. However, it goes on to say that it would be
"difficult" for applicants "as a scientific matter to establish
interchangeability in an original 351(k) application."
That general
wording has led some companies such as Sandoz, a leading biosimilar marketer in
Europe, to express disappointment in a lack of specifics with regard to
interchangeability requirements. "The FDA is the only regulatory body that has been provided with the
legal authority to allow interchangeability of substitution," explains Sreejit Mohan, Head Biopharma, Oncology &
Financ. Communications, Sandoz International GmbH. "In particular in the recently released draft
guidances, FDA has not clearly outlined how interchangeability could be
supported."
Momenta's Roach thinks the hurdle should
be high for the FDA to grant interchangeability. "However
nothing in draft guidance leads us to believe that achieving a designation of
interchangeability is an impossibility if we are able to present a compelling
and scientifically robust data package," he states. "But we don't
underestimate the complexity."
To
insure it has the staff to make timely decisions on biosimilarity and
interchangeability, the FDA has asked the Congress to authorize it to collect
user fees from biopharma companies who submit 351(k) applications. This Biosimilar User Fee Act (BsUFA) program would
impose fees
in different categories, but they essentially would add up to the fee a drug
company pays the FDA when it submits a new drug application for a conventional,
chemically synthesized drug under the Prescription Drug Users Fee Act (PDUFA)
program. In return for biosimilar fees, the FDA would commit to approving
351(k) applications in a certain timeframe. The biosimilar user fee program
will probably be approved as part of congressional passage of the fifth
iteration of PDUFA. Its current authorization expires by the end of September.
So Congress, theoretically, must renew it by then, and establishment of the BsUFA
would ostensibly be attached as an amendment.
While
biopharma companies do not question the need for a biosimilar user fee, they
have question the structure the FDA has proposed. Nikhil Mehta, Vice President,
Biologics Worldwide Regulatory Affairs, Merck, has raised questions about the
proposed $150,000 per IND application "development fee." That money
would be used to support FDA biosimilar programs generally. Then, the company
would get some sort of "credit" against that fee when it submitted a
marketing (IND) application. However, the FDA has not explained what would
happen if the biosimilar did not get beyond the IND phase. That would,
according to Mehta, leave drug companies "with no way to recoup the
additional cost burdens associated with this unique development fee if the
product was discontinued." Another issue is what happens if the FDA deems
a product "not biosimilar." Failure to resolve these issues, Mehta
says, "will serve as disincentives to utilizing the biosimilar
pathway."
But both innovator and generic drug
companies are in basic support of a BsUFA as long as Congress does not make the
351(k) program dependent on those user fees only. David Wheadon, M.D., Senior
Vice President, Scientific and Regulatory Affairs, Pharmaceutical Research and
Manufacturers of America, says user fees should supplement, rather than
replace, congressional appropriations. Sara Radcliffe , Executive Vice President, Health,
Biotechnology Industry Organization, Washington, DC, says whatever user fees
that are collected annually should be in addition to $20 million a year
Congress appropriates for the program. .
It is too early to bestow industry
blessings on both the final guidance and the BsUFA program. Neither will be in
place for a few months, probably. But regardless how the bricks are laid on the
new 351(k) pathway, biopharma companies will eventually be skipping down it
like Dorothy and company down the Yellow Brick Road. They won't be off to see
The Wizard, of course. But they will hope to be successful with some biological
wizardry of their own.
