FDA is working to develop guidelines for documenting the similarity and interchangeability of copycat versions of biotech
therapies, a process that is drawing considerable scrutiny from a broad spectrum of manufacturers. There are a host of thorny
issues to resolve related to reference products, interchangeability, labeling, and exclusivity. One area of agreement is that
producing biosimilars is vastly more complex and costly than manufacturing conventional generic drugs, and that FDA will require
broader testing to license a product as biosimilar or interchangeable. Developing a follow-on biotech therapy will require
considerable investment in time, resources, and expertise, running up a tab of some $75–$250 million and typically taking
seven to eight years, according to Ameet Mallik, global head of Novartis's Sandoz biopharmaceutical division, during an investor
call in May 2011.
Even so, the prospect of biopharmaceuticals capturing a greater share of the global drug market is drawing interest from many
pharmaceutical and biotech companies. The worldwide market for biosimilars is projected to grow to $3.7 billion by 2015, up
from about $250 million last year, according to Datamonitor. As more biotechnology product patents expire and regulatory authorities
clarify requirements, biosimilar development is projected to soar. Leading pharmaceutical companies, such as Novartis and
Merck, aim to be major players in the field, and even innovator biotech companies like Amgen are eyeing the follow-on market.
Setting a pathway
FDA officials are under pressure from Congress, government agencies, and payers to develop an abbreviated regulatory pathway
for approving biosimilars, as authorized by the Biologics Price Competition and Innovation Act (BPCI), which was approved
as part of the Affordable Care Act (ACA) of 2010. The legislation aims to reduce spending on prescription drugs by permitting
"highly similar" versions of biotech therapies to come to market based on less-extensive nonclinical and clinical data than
was required to approve the original reference drug. Manufacturers talk of marketing biosimilars at discounts of 25–30% off
branded products, but reimbursement experts say that prices that are just 10% lower will be able to gain market share, particularly
for therapies that have high price tags to start.
BPCI gives FDA the task of establishing a process that will encourage development of biosimilars that meet all standards for
product safety, purity, and potency. No "clinically meaningful differences" should exist between the new biologic and the
reference product. Both should use the same mechanism of action and have the same route of administration, dosage form, and
strength (see sidebar, "Ensuring comparabiliy and similarity"). A biosimilar also has to be manufactured, processed, packaged,
and stored in facilities that meet GMP standards.
FDA began the formal guidance-development process for evaluating biosimilars at a November 2010 public meeting. Janet Woodcock,
director of the Center for Drug Evaluation and Research (CDER), recently indicated that general guidance should appear before
the end of 2011, and that requirements for human testing will vary according to how well a biosimilar can document similarity
to the innovator product.
In Washington this month
FDA also is moving forward with a user-fee schedule for biosimilars. The agency proposes to set fees similar to those for
innovator drugs and biologics, but will take a new approach to help finance FDA's extensive involvement in steering sponsors
through the development process. The plan is for manufacturers to pay a product development fee of $150,000 with submission
of an investigational new drug application and annually thereafter; those upfront payments would be subtracted from the eventual
application fee. Performance goals for approving applications would apply to applications submitted within two years of the
expiration of exclusivity for the reference product, but not to applications for products that have years to wait before they
can enter the market.
The application process
. Even without final guidance, FDA officials say they're ready to evaluate biosimilar applications on an individual basis.
"We were open for business a year ago," said Steven Kozlowski, director of CDER's Office of Biotechnology Products, at the
"Future of Biosimilars" conference in May 2011, jointly sponsored by the Drug Information Association (DIA) and the Food and
Drug Law Institute (FDLI). So far, no manufacturers have attempted the 351(k) approval route for biosimilars authorized by
BPCI and are instead continuing to use established drug-approval procedures for some follow-on versions of proteins. If FDA
testing requirements and other policies make the biosimilars pathway too arduous, manufacturers say they may use the traditional
biologic license application (BLA) and sidestep the 351(k) route altogether.
In devising guidance, FDA has to tackle some basic issues, such as which products fall under the new regulatory program. BPCI
extends the definition of biologics to most proteins beginning in March 2020. That definition raises questions about how the
change will affect manufacturers of human growth hormones and other proteins, and how they should proceed during the nine-year
A thorny subject is whether FDA can approve a biosimilar based on a reference product that is approved overseas, but not in
the United States. BPCI says that reference products have to be licensed by FDA, but biosimilars manufacturers want flexibility
to permit comparison with a biologic licensed by a foreign regulatory body under certain circumstances. This approach is important
for global biosimilar-development programs, pointed out John Pakulski, head of US biopharmaceutical regulatory affairs at
Sandoz, at the DIA/FDLI conference. If every country or region requires local trials using locally sourced products, he observed,
that could undermine efforts to establish a less-costly abbreviated development program.
Pakulski and others propose a science-based approach that permits the use of foreign reference products when they are made
by a US manufacturer or in a facility inspected by FDA; licensed in highly regulated markets, such as Europe or Japan; and
have a sufficient postmarketing history to confirm safety, purity. and potency. Additional scientific data could be required
on a case-by-case basis to establish comparability between a US and foreign-sourced reference product.
Another contentious question is whether biosimilar manufacturers can extrapolate data from a clinical study to other indications
of the reference product. European regulatory authorities permit this if the added indication involves the same mechanism
of action and same receptor, and if extrapolation of immunogenicity data applies to a lower-risk population or route of administration.
Biosimilar-drug sponsors indicate that extrapolation may be appropriate if supported by open-label safety studies for each