The only area of agreement about developing and regulating follow-on biotech therapies is that the process is more complex
and more costly than for conventional generic drugs, and that the Food and Drug Administration (FDA) will require more testing
to label a product biosimilar or interchangeable. Developing a biosimilar will cost $75 million to $250 million and take seven
to eight years, according to those experienced in the field.
Even so, the growth prospects for biopharmaceuticals makes follow-on development increasingly attractive to diverse players.
The worldwide market for biosimilars is projected to grow to $3.7 billion by 2015, up from about $250 million last year, reports
Datamonitor. As more biotech patents expire and regulatory authorities clarify the rules, development of copycat therapies
is slated to soar. Payers talk of biosimilars offering discounts of 25 percent to 30 percent off brands, but reimbursement
experts say that prices that are just 10 percent lower will be able to gain market share, particularly for therapies with
high price tags to begin with (see sidebar).
Codes and coverage
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 (BPCIA), part of the Affordable
Care Act of 2010. The legislation aims to reduce spending on pharmaceuticals by bringing "highly similar" versions of biotech
therapies to market based on less extensive preclinical and clinical testing than was required to approve the original reference
The challenge for FDA is to establish science-based standards for documenting biosimilar safety, purity, and potency that
acknowledges reference drug data and market experience. FDA held a public meeting in November 2010 to launch the process for
establishing a biosimilar testing process to ensure there are no "clinically meaningful differences" between the new biologic
and the reference product; the new drug has to use the same mechanism of action and have the same route of administration,
dosage form, and strength. Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER), recently indicated
that general guidance should appear this year, and that its requirements for human testing will vary according to how well
a biosimilar can document sameness to the innovator product. Although biosimilars generally will need additional clinical
studies to document equivalent efficacy in at least one approved indication, even innovator firms acknowledge that the biosimilar
pathway will involve less animal toxicity testing and probably no dose finding or Phase II clinical studies.
Another key step is to set a user fee schedule for biosimilars. The agency has proposed application fees similar to those
for innovator drugs and biologics, but with a new approach to help finance FDA involvement in steering sponsors through the
development process. The plan is for companies to pay a product development fee of $150,000 when it submits an investigational
new drug application and annually thereafter; those upfront payments then will be subtracted from the eventual application
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 a May biosimilars
conference, 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 authorized by the BPCIA, but many are talking to FDA and considering
Meanwhile, FDA is tackling some very basic issues, such as which products fall under the new regulatory program. The BPCIA
redefines most proteins as biologics, beginning in March 2020. FDA thus has to set new policies for manufacturers of proteins
long regulated as drugs and address the nine-year transition period.
Another thorny topic is whether FDA can approve a biosimilar based on a reference product that is approved overseas, but not
in the US. The BPCIA says that reference products have to be licensed by FDA, but biosimilar makers want flexibility to permit
comparison to a biologic licensed by a foreign regulatory body. This is important for global biosimilar development programs,
pointed out John Pakulski, head of US biopharmaceutical regulatory affairs at Sandoz, at the DIA/FDLI conference. He and others
propose to permit the use of foreign reference products that are made by a US manufacturer or in a facility inspected by FDA;
licensed in highly regulated markets such as Europe or Japan; or present 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.
Also contentious is whether biosimilar sponsors 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
sponsors want a similar approach from FDA, probably with support from open-label safety studies for each indication.