A key challenge for FDA is to define interchangeability testing requirements and whether clinical switching studies will be
required. Manufacturers want products to qualify as interchangeable because the first follow-on biologic so deemed by FDA
enjoys a year of market exclusivity, during which FDA may not approve another similar interchangeable product. The designation
also is important for acceptance by patients and healthcare professionals, and for possible substitution by pharmacists and
Gordon Johnson, vice-president of the Generic Pharmaceutical Association, noted at the DIA/FDLI meeting that switching studies
are not required for innovator manufacturers to document comparability following postapproval changes. Gillian Woollett, chief
scientist at the law firm Engel & Novitt, added during the conference that documenting comparability to the innovator inherently
supports a finding on interchangeability. Innovator biologics experience batch-to-batch variability over the product's life
time, Woollett observed, and that kind of variability should be accepted in biosimilars.
Yet, innovators maintain that clinical studies in multiple populations with different risk–benefit profiles are necessary
to document that there are no greater risks of safety problems or efficacy differences with product switching. Amgen Vice-President
Anthony Mire-Sluis maintained that head-to-head studies are needed to compare immunogenicity between reference and follow-on
biotechnology products, and that different assays can yield different rates of immunogenicity. He also wants product labels
to state explicitly the approved indications of a therapy and whether a biosimilar is interchangeable for that use.
The potential for product naming and coding to drive coverage and reimbursement generates heated debate on those topics. Innovator
firms maintain that biosimilars should have unique names to distinguish them from reference products, an issue that BPCI failed
to address. Different names can ensure traceability of adverse events, reduce confusion about interchangeability, and prevent
Biosimilar advocates prefer names linked to a reference product to "make clear to prescribers and patients that the products
are related," explained attorney Erika Lietzan of Covington & Burling during the conference. Some physicians propose unique
names only for noninterchangeable biosimilars. European Union guidance calls for biosimilars to have different names, but
most relate to innovator products. FDA officials may seek to promote safety with names that differentiate similar versions
of a drug.
Ensuring comparability and similarity
Product coding raises related issues. Innovators want biosimilars to have their own reimbursement codes, while biosimilars
makers want the same code for all drugs in the same class. A dozen human growth hormone products have the same Medicare reimbursement
code and thus receive the same rate of reimbursement, explained attorney Laura Loeb of King & Spalding. But even without interchangeability
status and common codes, Loeb predicts that it will be difficult for more expensive reference products to maintain market
share. Formulary committees and state Medicaid programs, she points out, can drive prescribing through formulary placement,
higher copays, prior authorization, and requiring-step therapy procedures for reference products. "The burden will be on the
reference product to prove superiority to the biosimilar," Loeb observed, "not the other way around."
Even though BPCI provides 12 years' exclusivity for innovator biologics, a period when FDA cannot approve a product based
on innovator data, the subject is far from settled. Innovators also gain a four-year delay following reference-product licensure
during which time biosimilars sponsors cannot submit a 351(k) application. Biotech companies consider these protections crucial
for encouraging investment in research and development. Critics, however, claim that 12 years exclusivity is too long, and
the Obama administration recently proposed reducing exclusivity to 7 years.
The shorter protection period also aims to minimize exclusivity "evergreening," which refers to the practice of manufacturers
seeking an additional period of protection for products that are modified enough to qualify as new. FDA has to define what
changes would sufficiently affect a product's safety, purity, or potency to warrant extended exclusivity. The change has to
be significant, says Kozlowski of CDER. "I don't think that 'slightly better purity' is enough to extend exclusivity," he
observed at the DIA/FDLI conference.
As with conventional generic drugs, patent and exclusivity issues involving biosimilars are likely to generate extensive regulatory
maneuvering and lengthy court battles. Manufacturers on both sides of the market are expected to file citizens' petitions
challenging FDA's interpretation of BPCI, particularly regarding how it defines "biosimilar" and what constitutes "interchangeability."
The legislation establishes an even more complex system for dealing with patent and regulatory disputes than applies to conventional
generic drugs. Unlike the Hatch–Waxman Act, BPCI doesn't directly involve FDA in listing patents. Instead, the law requires
biosimilars developers to provide reference-product makers with a full dossier on its process and product so that the innovator
can identify those patents it feels may be infringed. This "hokey-pokey process," explained Sidley Austin Attorney Jeffrey
Kushan, was designed to promote early agreement on those patents worth fighting about. But Kushan fears it will create a more
complicated litigation process involving multiple deadlines and requirements that will please no one. Biosimilars makers complain
that too many parties will see their confidential regulatory filings, while BLA-holders stand to lose protection if they fail
to follow all the rules. If the 351(k) process becomes too contentious and costly as a result, biosimilars sponsors may opt
to follow the traditional BLA route to market, which offers the reward of 12 years' exclusivity.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, email@example.com