FDA and Manufacturers Ponder Biosimilars Pathway - Pharmaceutical Technology

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FDA and Manufacturers Ponder Biosimilars Pathway
Follow-on versions of complex biologics require extensive expertise in development and regulatory procedures.

Pharmaceutical Technology
Volume 35, Issue 7, pp. 28-32

Interchangeability issues

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 prescribers.

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 dispensing errors.

Ensuring comparability and similarity
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.

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,


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