FDA and Manufacturers Ponder Biosimilars Pathway

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Pharmaceutical Technology, Pharmaceutical Technology-07-02-2011, Volume 35, Issue 7

Follow-on versions of complex biologics require extensive expertise in development and regulatory procedures.

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.

Jill Wechsler

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


User fees. 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 transition period.

Reference products. 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 indication.

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.

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, jwechsler@advanstar.com.